Compounds for use as GPR120 agonists

ABSTRACT

The present invention relates to a compound of formula (I), or a tautomer, stereoisomer, geometrical isomer, prodrug, carboxylic acid isostere, solvate, polymorph, N-oxide, S-oxide or pharmaceutically acceptable salt thereof, which are GPR120 agonists. The present invention also relates to a pharmaceutical composition of a compound of formula (I) for the treatment of metabolic disorders, particularly Type 2 diabetes and associated diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. national stage application of InternationalPatent Application No. PCT/IB2015/051232, filed on Feb. 18, 2015, whichclaims priority to U.S. Provisional Application No. 61/941,794, filed onFeb. 19, 2014, the contents of each of these applications isincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to compounds of formula (I) (as describedherein), processes for their preparation, pharmaceutical compositionscomprising the compounds, and methods for their use for the prophylaxisand/or treatment of the diseases or disorders which are mediated byGPR120 receptor.

BACKGROUND OF THE INVENTION

Metabolic diseases or disorders are caused by an abnormal metabolicprocess and may either be congenital due to an inherited enzymeabnormality or acquired due to a disease of an endocrine organ orfailure of a metabolically important organ such as the liver or thepancreas.

Among the metabolic disorders, diabetes mellitus is the most prevalentand is considered to be one of the five leading causes of death in theworld (Diabetes Care, vol. 27, 2004, pp. 1047-1053). Diabetes mellitusis typically classified into two main subtypes: Type 1 and Type 2diabetes mellitus. Type 1 diabetes mellitus (otherwise known as InsulinDependent Diabetes Mellitus, IDDM), which generally occurs inadolescents under 20 years of age, is an auto-immune disease causing aninsulitis with the subsequent destruction of insulin-producing β-cellsof the pancreas. Further, in latent autoimmune diabetes in adults(LADA), β-cells are destroyed due to autoimmune attack. The subsequentlack of insulin leads to elevated levels of blood and urine glucose(hyperglycemia). Although the exact trigger for this autoimmune responseis not known, patients with Type 1 diabetes have high levels ofantibodies against pancreatic beta cells (hereinafter “beta cells”).However, it cannot be ascertained that all patients with high levels ofthese antibodies develop Type 1 diabetes. Type 2 diabetes mellitus ornon-insulin-dependent diabetes mellitus (NIDDM) is developed when humanmuscle, fat and liver cells are not able to respond normally to insulinthat body secretes. This inability to respond, otherwise known asinsulin resistance, may be due to restriction on the numbers of insulinreceptors on these cells, or a dysfunctional behaviour of signallingpathways within the cells, or both. Initially, the β-cells which areresponsible for the production of insulin, compensate for this insulinresistance by increasing their insulin secretion. However, these cellsgradually become unable to produce enough insulin to facilitate thenormal glucose homeostasis, causing the progression to Type 2 diabetes(Am J Med. 108(6), Supplement 1, 2000, pp. 2S-8S). Type 2 diabetes (T2D)is characterised by fasting hyperglycemia which occurs as an effect ofthe combined lesions of insulin resistance and β-cell dysfunction. Thereare two types of defects associated with the β-cells: the firstcomponent, an increase in the basal insulin release which usually occursin the presence of low, non-stimulatory glucose concentrations. Thesecond component is a failure to enhance the insulin release in responseto a hyperglycaemic challenge.

Obesity is another risk factor for developing metabolic diseases ordisorders such as diabetes, cardiovascular disorders, hypertension,hyperlipidemia and an increased mortality. Diabetes caused by insulinresistance and obesity are part of the “metabolic syndrome” which isdefined as the linkage between several diseases (also referred to assyndrome X, insulin-resistance syndrome, or deadly quartet). These oftenoccur in the same patients and are major risk factors for thedevelopment of Type 2 diabetes and cardiovascular diseases (Frontiers inEndocrinology, vol. 4, 2013, pp. 1-11). It has been suggested that thecontrol of lipid levels and/or glucose levels is required to treat type2 diabetes and cardiovascular diseases. Even though lifestyle changeslike exercise and healthy diet are regarded as the most efficient waysto prevent and manage the disease, pharmaceutical intervention isfrequently necessary.

Current treatment options for diabetes, particularly T2D include use ofhypoglycaemic agents and insulin. Metformin is one such hypoglycemicagent which is used in the treatment of Type 2 diabetes. It is, in fact,one of the oldest drugs used for the treatment of T2D and it stillremains the drug of choice despite associated gastrointestinal (GI) sideeffects including anorexia, nausea, diarrhea and vomiting commonlyassociated with it. In fact, metformin should be used with caution inpatients with renal impairment because of the slight risk of lacticacidosis. Sulfonylureas (SUs) e.g. glimepiride, glipizide, are insulinsecretagogues, which act on β-cells to increase insulin release, arecommonly used in the treatment of Type 2 diabetes. However, use ofsulfonylureas is also associated with adverse effects in that theyincrease the risk of hypoglycaemia and lead to weight gain. Insulintreatment which is chosen by patients carries the same side-effects.Thiazolidinedione compounds e.g. rosiglitazone, pioglitazone, areinsulin sensitizers which bind to peroxisome proliferator-activatedreceptors (PPARs) in cells and thereby increase the insulin sensitivity.Though, thiazolidinedione compounds have also been widely used, theenhanced risks of cardiovascular disease and hepatotoxicity haveresulted in stringent limitations on their use. Relatively recently,regulatory authorities approved new classes of anti-diabetic agents suchas GLP-1 agonists (exenatide and liraglutide) and DPP-4 inhibitors(linagliptin and alogliptin).

It is a known fact that metabolic processes are regulated by fatty acidswhich are important biological molecules that serve both as a source ofenergy and as signalling molecules. Generally, it is believed that fattyacids produce their biological effects through interacting withintracellular targets including, for example, the family of peroxisomeproliferator-activated receptors (PPARs). However, in the recent yearsit has become clear that fatty acids also serve as agonists for a groupof cell surface G protein-coupled receptors (GPCRs). Free fatty acids(FFAs) have been demonstrated to act as ligands of several GPCRsincluding GPR40 (FFAR1), GPR43, GPR84, GPR119 and GPR120. One of theGPCR namely GPR40 facilitates glucose-stimulated insulin secretion frompancreatic β-cells, whereas the other GPCR namely GPR120 regulates thesecretion of glucagon-like peptide-1 (GLP-1) in the intestine, as wellas insulin sensitivity in macrophages. GPR120 is localized to intestinalenteroendocrine cells, such as colonic L cells. Certain research studiesconducted relative recently, identified that loss-of-function GPR120human variant is associated with obesity, diabetes and other insulinresistance, and related metabolic disorders and also with inflammatorydisorders. These findings establish GPR120 as a potential target for thetreatment of diabetes, other metabolic disorders and also, inflammatorydisorders (Trends Pharmacol Sci. vol. 32(9), 2011 pp. 543-550).

Thus, in view of the role of GPR120 receptor in potentiating metabolicdisorders such as diabetes and also, inflammatory disorders, there isneed in the art to develop compounds that act by modulating the GPR120receptor pathways.

Various patent documents describe compounds which are reported to beGPR120 modulators. Examples of patent documents describing GPR120modulators include PCT Application Publications WO2008103500,WO2009038204, WO2010008831, WO2010048207, WO2010080537, WO2010104195,WO2011072132, WO2013139341 and WO2013185766; European Published PatentApplication EP2125758A1; US Published Patent Application US2011065739and U.S. Pat. No. 8,367,708.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to a compound of formula(I) (as described herein) or a tautomer, a stereoisomer or a geometricalisomer thereof; or pharmaceutically acceptable salt, a pharmaceuticallyacceptable solvate, a prodrug, a polymorph, an N-oxide, a S-oxide or acarboxylic acid isostere thereof.

In another aspect of the present invention, there is provided a processfor the preparation of the compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

In a further aspect, the present invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula (I) or a stereoisomer, a tautomer or a geometrical isomerthereof or a pharmaceutically acceptable salt or a pharmaceuticallyacceptable solvate thereof; and at least one pharmaceutically acceptablecarrier or excipient.

In a further aspect, the present invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula (I) or a pharmaceutically acceptable salt thereof; and onefurther therapeutically active agent and at least one pharmaceuticallyacceptable carrier or excipient.

In another further aspect, the present invention relates to a method formodulating GPR120 function in a cell.

In yet another aspect, the present invention provides a compound ofFormula (I) or a stereoisomer, a tautomer or a geometrical isomerthereof or a pharmaceutically acceptable salt or a pharmaceuticallyacceptable solvate thereof; for use in the treatment or prophylaxis of adisease or a disorder mediated by GPR120.

In yet another further aspect, the present invention provides a methodfor the treatment or prophylaxis of a disease or a disorder mediated byGPR120, comprising administering to a subject in need thereof; atherapeutically effective amount of the compound of Formula (I) or astereoisomer, a tautomer or a geometrical isomer thereof or apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof.

In a still further aspect, the present invention relates to use of thecompound of Formula (I) or a stereoisomer, a tautomer or a geometricalisomer thereof or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof; in the manufacture of amedicament, for the treatment or prophylaxis of a disease or a disordermediated by GPR120.

In another further aspect, the present invention relates to use of thecompound of Formula (I) or a stereoisomer, a tautomer or a geometricalisomer thereof or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof; in combination with onefurther therapeutically active agent for the treatment or prophylaxis ofa disease or a condition mediated by GPR120.

These and other objectives and advantages of the present invention willbe apparent to those skilled in the art from the following description.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention relates to a compound offormula (I),

or a tautomer, a stereoisomer or a geometrical isomer thereof; orpharmaceutically acceptable salt, a pharmaceutically acceptable solvate,a prodrug, a polymorph, an N-oxide, a S-oxide or a carboxylic acidisostere thereof;wherein:

Ring A is a saturated or unsaturated 4- to 10-membered carbocycle; a 5-to 10-membered heteroaryl; or a saturated or partly saturated orunsaturated 5- to 10-membered heterocycle; wherein said heteroaryl orheterocycle contain 1, 2, 3 or 4 heteroatoms independently selected fromN, O and S;

Ring B and Ring C are independently selected from the group consistingof (C₆-C₁₀)aryl and 6- to 10-membered heteroaryl which contains 1, 2 or3 heteroatoms independently selected from the group consisting of N, Oand S;

X is —(CR⁸R⁹)_(p)—O—, —(CR⁸R⁹)_(p)—S—, —(CR⁸R⁹)_(p)—N(R¹⁰)—,—O—(CR⁸R⁹)_(p)—, —S—(CR⁸R⁹)_(p)— or —N(R¹⁰)—(CR⁸R⁹)_(p);

Y is —(CR¹⁴R¹⁵)_(g)—;

Q is CO₂M, —CONH₂, —CONH[(C₁-C₆)alkyl], —CON[(C₁-C₆)alkyl]₂ or—CONHSO₂(C₁-C₆)alkyl;

M is hydrogen, deuterium or (C₁-C₆)alkyl;

R¹ is

wherein

-   is point of attachment to ring A;-   J is —CH₂—, —CHF—, —CF₂—, —C[(C₁-C₆)alkyl]₂-, —O—, —NR^(a)— or —S—;    “—” represents an optional bond;-   R^(a) is hydrogen, (C₁-C₆)alkyl or halo(C₁-C₆)alkyl;

R² is selected from the group consisting of hydrogen, halogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heteroaryl, heterocyclyl,(C₆-C₁₀)aryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,heterocyclyl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heterocyclyl,heteroaryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heteroaryl, cyano, —NR¹⁰R¹¹,—C(O)NR¹⁰R¹¹, —C(S)NR¹⁰R¹¹, —S(O)_(t)R¹² and —C(O)R¹³;

-   or-   R¹ and R² are combined together with one or two atoms of Ring A to    form:-   i) a 3- to 8-membered partly unsaturated or saturated carbocycle; or-   ii) a 3- to 8-membered saturated heterocycle which contains 1, 2 or    3 heteroatoms independently selected from the group consisting of N,    O and S;-   wherein the said carbocycle or heterocycle can be unsubstituted or    substituted with one or more groups independently selected from the    group consisting of (C₁-C₆)alkenyl, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,    (C₁-C₆)alkoxy, hydroxy, halogen, cyano, oxo, (C₃-C₁₀)cycloalkyl,    (C₆-C₁₀)aryl, heteroaryl and heterocyclyl;

R³ at each occurrence, is independently selected from the groupconsisting of hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heteroaryl,heterocyclyl, (C₆-C₁₀)aryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, heterocyclyl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heterocyclyl-,heteroaryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heteroaryl, cyano, —NR¹⁰R¹¹,—C(O)NR¹⁰R¹¹, —C(S)NR¹⁰R¹¹, —S(O)_(t)R¹² and —C(O)R¹³;

R⁴, at each occurrence, is independently selected from the groupconsisting of hydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy,hydroxy, halogen, cyano, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heteroaryl,heterocyclyl, (C₆-C₁₀)aryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, heterocyclyl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heterocyclyl,heteroaryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heteroaryl, —NR¹⁰R¹¹, —S(O)_(t)R¹²and —C(O)R¹³;

R⁵ is selected from the group consisting of hydrogen, (C₁-C₆)alkyl,hydroxy, cyano, —COR¹⁰, —NR¹⁰R¹¹, —CONR¹⁰R¹¹, (C₁-C₆)alkylamino,di(C₁-C₆)alkyl amino, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, —S(O)_(t)R¹² and—C(O)R¹³;

R⁶ and R⁷ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and halogen;

R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, deuterium, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and halogen; or

R⁸ and R⁹ can combine together to form

-   i) a 3- to 5-membered saturated carbocycle selected from the group    consisting of cyclopropane, cyclobutane, cyclopentane and    cyclohexane; or-   ii) a 4- to 6-membered saturated heterocycle selected from the group    consisting of oxetane, thietane, azetidine, tetrahydrofuran,    tetrahydrothiophene, pyrrolidine and piperidine;

R¹⁰ is hydrogen, hydroxy, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl,(C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C₆-C₁₀)aryl,heterocyclyl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heterocyclyl,heteroaryl-(C₁-C₆)alkyl or (C₁-C₆)alkyl-heteroaryl or —S(O)_(t)R¹²;

R¹¹ is hydrogen, hydroxy, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,heterocyclyl, heteroaryl, (C₆-C₁₀)arylox_(Y), (C₆-C₁₀)aryl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C₆-C₁₀)aryl, heterocyclyl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-heterocyclyl, heteroaryl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-heteroaryl or —S(O)_(t)R¹²; or

R¹⁰ and R¹¹ are combined together to form a 3- to 8-membered saturatedor unsaturated ring which contains 1, 2 or 3 heteroatoms independentlyselected from the group consisting of N, O and S;

R¹² and R¹³ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,(C₆-C₁₀)aryl, heterocyclyl, heteroaryl, (C₆-C₁₀)aryl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C₆-C₁₀)aryl, heterocyclyl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-heterocyclyl, heteroaryl-(C₁-C₆)alkyl and(C₁-C₆)alkyl-heteroaryl;

R¹⁴ and R¹⁵ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and halogen;

or

R¹⁴ and R¹⁵ are combined together to form a 3- to 5-membered saturatedcarbocycle or 4- to 6-membered saturated heterocycle which optionallycontains 1 or 2 heteroatoms independently selected from the groupconsisting of N, O and S; wherein the said carbocycle or heterocycle canbe substituted or unsubstituted.

-   g is 2, 3, 4, 5 or 6;-   m is 0, 1 or 2;-   n is 0, 1 or 2;-   p is 1, 2 or 3;-   r is 0, 1, 2, 3 or 4;-   t is 0, 1 or 2;-   wherein

(C₁-C₆)alkyl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₆-C₁₀) aryloxy, heterocyclyl,heteroaryl, amino, cyano, nitro, —NH(C₁-C₆)alkyl, —N[(C₁-C₆)alkyl]₂,—C(O)(C₁-C₆)alkyl, —C(O)O(C₁-C₆)alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl,—C(O)N[(C₁-C₆)alkyl]₂ and —C(O)NHSO₂(C₁-C₆)alkyl;

(C₃-C₁₀)cycloalkyl is unsubstituted or substituted with one or moregroups independently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,amino, cyano and nitro;

carbocycle is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, hydroxy, halogen, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl, heteroaryl, heterocyclyl, amino,cyano, nitro, —C(O)O(C₁-C₆)alkyl, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; whereinR¹⁰, R¹¹, R¹² and t are as defined above;

(C₆-C₁₀)aryl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, amino,cyano, nitro, —C(O)O(C₁-C₆)alkyl, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; whereinR¹⁰, R¹¹, R¹² and t are as defined above;

heterocyclyl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, amino,cyano, nitro, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and tare as defined above;

heteroaryl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,heterocyclyl, heteroaryl, amino, cyano, nitro, —C(O)NR¹⁰R¹¹ and—S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are as defined above.

Definitions

Unless otherwise indicated, the following definitions are set forth toillustrate and define the meaning and scope of the various terms used todescribe the invention herein and the appended claims. These definitionsshould not be interpreted in the literal sense as they are not intendedto be general definitions and are relevant only for this application.

The singular forms “a”, “an” and “the” include plural aspects unless thecontext clearly dictates otherwise. For instance, the terms “a”, “an”and “the” refers to “one or more” when used in the subjectspecification, including the claims. Thus, for example, reference to “acompound” may include a plurality of such compounds, or reference to “adisease” or “a disorder” includes a plurality of diseases or disorders.

It should also be noted that the term “or” is generally employed in itssense including “and/or” unless the content clearly dictates otherwise.

The term “independently” when used in the context of selection ofsubstituents for a variable, it means that where more than onesubstituent is selected from a number of possible substituents, thosesubstituents may be the same or different.

As used herein, the term “(C₁-C₆)alkyl” or “alkyl” as used herein; aloneor as part of a substituent group, refers to the radical of saturatedaliphatic groups, including straight or branched-chain alkyl groups. Astraight-chain or branched chain alkyl has six or fewer carbon atoms inits backbone, for instance, C₁-C₆ for straight chain and C₃-C₆ forbranched chain. As used herein, (C₁-C₆)-alkyl refers to an alkyl grouphaving 1 to 6 (both inclusive) carbon atoms; preferably refers to analkyl group having 1 to 4 (both inclusive) carbon atoms i.e.(C₁-C₄)-alkyl. Representative examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl,isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl and3-methylbutyl. In the “(C₁-C₆)alkyl” group, one or more carbon atoms canbe optionally replaced with one or more heteroatoms independentlyselected from N, O and S.

Furthermore, unless stated otherwise, the alkyl group can beunsubstituted or substituted with one or more groups; preferably with1-4 groups, independently selected from the group consisting of(C₁-C₆)alkyl, halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₆-C₁₀) aryloxy,heterocyclyl, heteroaryl, amino, cyano, nitro, —NH(C₁-C₆)alkyl,—N[(C₁-C₆)alkyl]₂, —C(O)(C₁-C₆)alkyl, —C(O)O(C₁-C₆)alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆)alkyl, —C(O)N[(C₁-C₆)alkyl]₂ and —C(O)NHSO₂(C₁-C₆)alkyl.

As used herein, the term “halo(C₁-C₆)alkyl” or “haloalkyl” refers to thealkyl group which is substituted with one or more halogens. Amonohalo(C₁-C₆)alkyl radical, for example, can have a chlorine, bromine,iodine or fluorine atom. Dihalo and polyhalo(C₁-C₆)alkyl radicals canhave two or more of the same or different halogen atoms. Representativeexamples of halo(C₁-C₆)alkyl include, but are not limited to,chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl,dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl and the like groups.

As used herein, the term “(C₁-C₆)-alkoxy” or “alkoxy” refers to a(C₁-C₆)-alkyl having an oxygen radical attached thereto. The term“(C₁-C₆)-alkoxy” or “O—(C₁-C₆)-alkyl” or alkoxy wherever used in thisspecification have the same meaning. Representative examples of alkoxygroups include, but are not limited to, methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, isobutoxy and t-butoxy. Furthermore, unless statedotherwise, the alkoxy groups can be unsubstituted or substituted withone or more groups. A substituted alkoxy refers to a (C₁-C₆)-alkoxysubstituted with 1-5 groups, preferably with 1-3 groups selected fromthe groups indicated above as the substituents for the alkyl group.

As used herein, the term “halogen” refers to chlorine, fluorine, bromineor iodine and is preferably, chlorine, bromine or fluorine.

The term “carbocycle” or “carbocyclic ring” refers to a saturated,partially unsaturated, unsaturated or aromatic 3 to 12 memberedmonocyclic or bicyclic ring systems whose ring atoms are all carbon, andthat the said carbocycle has a single point of attachment to the rest ofthe molecule. If the carbocycle is a bicyclic ring system, then any onering in the said bicyclic ring system is a 3-7 membered ring.Representative examples of carbocycle include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl,benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl,decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. “Aromaticcarbocycle” or “aromatic carbocyclic ring” refers to 3 to 12 memberedmonocyclic or bicyclic aromatic ring systems whose all ring atoms arecarbon.

The term “(C₆-C₁₄)-aryl” or “aryl” as used herein refers to monocyclicor bicyclic hydrocarbon groups having 6 to 14 ring carbon atoms,preferably 6 to 10 carbon atoms i.e. “(C₆-C₁₀)-aryl” in which thecarbocyclic ring(s) present have a conjugated pi electron system, whichmay be optionally substituted by one or more groups. Representativeexamples of (C₆-C₁₄)-aryl include, but are not limited to, phenyl,naphthyl, fluorenyl and anthracenyl.

Furthermore, unless stated otherwise, the aryl group can beunsubstituted or substituted with one or more groups. A substituted arylrefers to a (C₆-C₁₄)-aryl substituted with one or more groups,preferably 1 to 7 groups and more preferably 1 to 3 groups independentlyselected from the group consisting of (C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, amino,cyano, nitro, —C(O)O(C₁-C₆)alkyl, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; whereinR¹⁰, R¹¹, R¹² and t are as defined above.

As used herein, the terms “heterocycle”, “heterocyclyl” or“heterocyclic” whether used alone or as part of a substituent group,refers to a 3- to 12-membered, preferably 5- to 10-membered saturated orpartially unsaturated monocyclic, bicyclic or tricyclic ring systemcontaining 1 to 4 heteroatoms independently selected from oxygen,nitrogen and sulfur. Saturated heterocyclic ring systems do not containany double bond, whereas partially unsaturated heterocyclic ringsystems, can contain at least one double bond, but do not form anaromatic system containing a heteroatom. The oxidized form of the ringnitrogen and sulfur atom contained in the heterocyclyl to provide thecorresponding N-oxide, S-oxide or S,S-dioxide is also encompassed in thescope of the present invention. Representative examples of heterocyclylsinclude, but are not limited to, azetidinyl, acridinyl, benzodioxolyl,benzodioxanyl, dioxolanyl, indolizinyl, perhydroazepinyl,phenothiazinyl, phenoxazinyl, tetrahydroisoquinolinyl, piperidinyl,piperazinyl, homopiperazinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl,pyrrolidinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolinyl,isoindolinyl, octahydroindolyl, octahydroisoindolyl,decahydroisoquinolyl, benzopyranyl, morpholinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, tetrahydrofuryl, tetrahydropyranyl, chromanyland isochromanyl. When the heterocyclyl group represents “5- to10-membered heterocyclyl”, the representative examples include, but arenot limited to, benzodioxolyl, benzo[d][1,3]dioxolyl, benzodioxanyl,tetrahydroisoquinolinyl, piperidinyl, piperazinyl, homopiperazinyl,2-oxoazepinyl, 4-piperidonyl, pyrrolidinyl, oxazolinyl, oxazolidinyl,and morpholinyl.

Furthermore, unless stated otherwise, the heterocyclyl groups can beunsubstituted or substituted with one or more groups, preferably with1-7 groups, more preferably with 1-3 groups independently selected fromthe group consisting of (C₁-C₆)alkyl, halogen, halo(C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, amino, cyano, nitro,—C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are asdefined above.

As used herein, the term “heteroaryl” whether used alone or as part of asubstituent group, refers to 5- to 10-membered heterocyclyl having anaromatic ring containing one to four identical or different heteroatomsindependently selected from oxygen, nitrogen and sulfur atom.Representative examples of heteroaryls include, but are not limited to,pyrrole, pyrazole, imidazole, tetrazole, pyrazine, furan, thiophene,oxazole, oxadiazole, thiazole, benzimidazole, benzoxazole, triazole,benzothiazole, benzofuran, indole, isoindole, cinnoline, indazole,isoindole, thiadiazole, isoquinoline, benzoxazole, thiophene,benzothiazole, isoxazole, triazine, purine, pyridine, quinoline,isoquinoline, phenazine, oxadiazole, pteridine, carbazole, pyridazine,quinazolinyl, pyrimidine, isothiazole, quinoxaline (benzopyrazine),tetrazole, pyrido[2,3-b]pyrazine. The oxidized form of the ring nitrogenand sulfur atom contained in the heteroaryl to provide the correspondingN-oxide, S-oxide or S,S-dioxide is also encompassed in the scope of thepresent invention.

Furthermore, unless stated otherwise, the heteroaryl groups can beunsubstituted or substituted with one or more groups; preferably with1-7 groups, more preferably with 1-3 groups independently selected fromthe group consisting of (C₁-C₆)alkyl, halogen, halo(C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, heterocyclyl, heteroaryl,amino, cyano, representative examples of heteroaryl include, but are notlimited to, pyrrole, pyrazole, imidazole, pyrazine, furan, thiophene,triazole, benzothiazole, benzofuran, indole, purine, pyridine,quinoline, isoquinoline, pyridazine, quinazolinyl, pyrimidine andisothiazole.

As used herein, the term “(C₃-C₁₂)-cycloalkyl” or “cycloalkyl”, whetherused alone or as part of a substituent group, refers to a saturatedcyclic hydrocarbon radical including 1, 2 or 3 rings and including atotal of 3 to 12 carbon atoms forming the rings, which may be optionallysubstituted by one or more substituents. The term cycloalkyl includesbridged, fused and spiro ring systems. As used herein,(C₃-C₁₂)-cycloalkyl refers to a cycloalkyl group having 3 to 12 (bothinclusive) carbon atoms; preferably, refers to cycloalkyl group having 3to 10 (both inclusive) carbon atoms i.e. (C₃-C₁₀)-cycloalkyl; and morepreferably, refers to cycloalkyl group having 3 to 7 (both inclusive)carbon atoms i.e. (C₃-C₇)-cycloalkyl. Representative examples ofcycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, perhydronaphthyl, adamantyl, homoadamantyl,noradamantyl, norbornyl, bicyclo[2.1.0]pentanyl, bicyclo[2.2.1]heptyl,spiro[3.3]heptanyl and spiro[4.4]non-2-yl.

The term “tautomer” refers to the coexistence of two or more compoundsthat differ from each other only in the position of one (or more) mobileatoms and in electron distribution. In fact, tautomers are structuralisomers of different energies which are interconvertible via a lowenergy barrier. For example, proton tautomers (also known as prototropictautomers) include interconversions via migration of a proton, such asketo-enol and imine-enamine isomerizations.

The term “prodrugs” as used herein refers to any pharmacologicallyinactive or less active compound which, when metabolized or chemicallytransformed in vivo by a chemical or physiological process, e.g., aprodrug on being brought to the physiological pH or through enzymeaction is converted to the parent compound e.g. the compound of formula(I) of the present invention. For example, in the context of the presentinvention prodrugs can be esters of the compound of formula (I) which onmetabolism the ester group is cleaved to form the active compound offormula (I). Examples of esters include lower alkyl esters, such as themethyl or ethyl ester; carboxy-lower alkyl esters, such as thecarboxymethyl ester; nitrooxy- or nitrosooxy-lower alkyl esters, such asthe 4-nitrooxybutyl or 4-nitrosooxybutyl ester; and the like.

The phrase, “carboxylic acid isostere” refers to a functional group or amoiety that elicits similar physical, biological and/or chemicalproperties as a carboxylic acid moiety. Representative examples ofcarboxylic acid isostere include, but are not limited to:

wherein R is hydrogen or (C₁-C₃)alkyl.

As used herein, the term “pharmaceutically acceptable” means that thecarrier, diluent, excipient, and/or salt must be compatible with theother ingredients of the formulation, and not deleterious to therecipient thereof.

The term “pharmaceutically acceptable salt(s)” as used herein includes asalt or salts of the active compound i.e. the compound of formula I,which retain the desired biological activity of the subject compound andexhibit minimal undesired toxicological effects; and are prepared withsuitable acids or bases, depending on the particular substituents foundon the compounds described herein.

Within the context of the present invention and as used herein “N-oxide”refers to the oxide of the nitrogen atom of a nitrogen-containingheteroaryl or heterocycle. N-oxide can be formed in the presence of anoxidizing agent for example peroxide such as m-chloro-perbenzoic acid orhydrogen peroxide. N-oxide refers to an amine oxide, also known asamine-N-oxide, and is a chemical compound that contains N→O bond.

Within the context of the present invention and as used herein “S-oxide”refers to the oxide of the sulfur atom (S-oxide) or dioxide of thesulfur atom (S,S-dioxide) of a sulfur-containing heteroaryl orheterocycle. S-oxide and S,S-dioxides can be formed in the presence ofan oxidizing agent for example peroxide such as m-chloro-perbenzoic acidor oxone.

Within the context of the present invention and as used herein, the term“solvate” or “solvates” describe a complex wherein the compound ofFormula (I) of the present invention, is coordinated with a proportionalamount of a solvent molecule. Specific solvates, wherein the solvent iswater, are referred to as hydrates.

Within the context of the present invention and as used herein the term“polymorph” or “polymorphic form” or “polymorphs” refer to crystals ofthe same compound that differs only in the arrangement and/orconformation of the molecule in the crystal lattice.

The term “subject” as used herein refers to an animal, preferably amammal, and most preferably a human. The term “mammal” used hereinrefers to warm-blooded vertebrate animals of the class ‘mammalia’,including humans, characterized by a covering of hair on the skin and,in the female, milk-producing mammary glands for nourishing the young.The term mammal includes animals such as cat, dog, rabbit, bear, fox,wolf, monkey, deer, mouse, pig and human.

As used herein, the terms “treatment” “treat” and “therapy” and the likerefer to alleviate, slow the progression, attenuation, or as such treatthe existing diseases or condition (e.g. diabetes). Treatment alsoincludes treating, or alleviating to some extent, one or more of thesymptoms of the diseases or condition.

The term “prophylaxis”, “prevention” or “preventing” can be usedinterchangeably and mean preventing the disease or disorder by causingthe clinical symptoms of the conditions, diseases, disorders orsyndromes to not develop or decreasing the development of the disease ordisorder or preventing the further development of the disease ordisorder in the subjects (the patients).

The term “compound(s) for use” as used herein embrace any one or more ofthe following: (1) use of compound(s), (2) method of use of compound(s),(3) use in the treatment of, (4) the use for the manufacture ofpharmaceutical composition/medicament for treatment/treating or (5)method of treatment/treating/preventing/reducing/inhibiting comprisingadministering an effective amount of the active compound to a subject inneed thereof.

The term, “therapeutically effective amount” as used herein means anamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof or a composition comprising a compound of formula (I) or asalt thereof, effective in producing the desired therapeutic response ina particular patient (subject) suffering from a disease or disordermediated by GPR120. An example of a disease or disorder mediated byGPR120 is diabetes such as type 2 diabetes. Particularly, the term“therapeutically effective amount” includes the amount of a compound (inthe context of the present invention, the compound of formula (I) or apharmaceutically acceptable salt thereof), when administered thatinduces a positive modification in the disease or disorder to be treatedor is sufficient to prevent development of, or alleviate to some extentone or more of the symptoms of the disease or disorder being treated ina subject. In respect of the therapeutic amount of the compound,consideration is also given that the amount of the compound used for thetreatment of a subject is low enough to avoid undue or severe sideeffects, within the scope of sound medical judgment. The therapeuticallyeffective amount of the compound or composition will vary with theparticular condition (in the context of the present invention, thedisease or disorder that is mediated by GPR120) being treated, the ageand physical condition of the subject, the severity of the conditionbeing treated or prevented, the duration of the treatment, the nature ofconcurrent therapy, the specific compound or composition employed, theparticular pharmaceutically acceptable carrier utilized and otherrelated factors.

Within the context of the present invention and as used hereininterchangeably throughout this application, the terms “compounds ofFormula (I)”, and “compounds of the present invention” include all thestereoisomeric and tautomeric forms and mixtures thereof in all ratios,and their pharmaceutically acceptable salts, solvates, polymorphs,prodrugs, carboxylic acid isosteres, N-oxides and S-oxides. Further, inthe context of the present invention, reference to the compounds ofFormula (I) includes reference to the compounds presented herein in oneor more embodiments either as such or represented by one or morestructural formula.

Within the context of the present invention and as used herein, the term“GPR120 agonist” or “GPR120 agonists” refer to the compound(s) ofFormula (I) of the present invention or a tautomer, a stereoisomer or ageometrical isomer thereof; or pharmaceutically acceptable salt, apharmaceutically acceptable solvate, a prodrug, a polymorph, an N-oxide,a S-oxide or a carboxylic acid isostere thereof; which binds to,activates, increases, stimulates, potentiates, sensitizes or upregulatesGPR120 receptor and promotes glucose induced insulin secretion.

The term “optionally substituted” means “substituted or unsubstituted,”and therefore, the generic structural formulae described hereinencompasses compounds containing the specified optional substituent aswell as compounds that do not contain the optional substituent.

Embodiments

According to one embodiment, the present invention encompasses acompound of Formula (I); wherein

-   R¹ is

wherein

-   is point of attachment to ring A;-   J is —CH₂—, —CHF—, —CF₂—, —CH[(C₁-C₆)alkyl]-, —C[(C₁-C₆)alkyl]₂-,    —O—, —NR^(a)— or —S—;-   “-----” represents an optional bond;-   R^(a) is hydrogen, (C₁-C₆)alkyl or halo(C₁-C₆)alkyl;

R² is independently selected from the group consisting of hydrogen,halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,(C₆-C₁₀)aryl, heteroaryl, heterocyclyl, (C₆-C₁₀)aryl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C₆-C₁₀)aryl-, heterocyclyl-(C₁-C₆)alkyl-,(C₁-C₆)alkyl-heterocyclyl, heteroaryl-(C₁-C₆)alkyl-,(C₁-C₆)alkyl-heteroaryl-, cyano, —C(O)NR¹⁰R¹¹, —C(S)NR¹⁰R¹¹,—S(O)_(t)R¹² and —C(O)R¹³;

R⁵, R⁶, R⁷ and r are as defined above.

According to one embodiment, the present invention encompasses acompound of Formula (I); wherein:

R¹ and R² are combined together with one or two atoms of Ring A to form:

-   i) a 3- to 8-membered, partly saturated or saturated carbocycle; or-   ii) a 3- to 8-membered, saturated heterocycle which contains 1, 2 or    3 heteroatoms independently selected from the group consisting of N,    O and S;    wherein the said carbocycle or heterocycle can be unsubstituted or    substituted with the one or more groups independently selected from    (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, halogen,    cyano, (C₆-C₁₀)aryl, heteroaryl and heterocyclyl.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring A is 6- to 10-membered aromaticcarbocycle; a 5- or 6-membered heteroaryl; or a 5- or 6-memberedheterocyclyl wherein the heteroaryl and heterocyclyl contain 1, 2 or 3heteroatoms independently selected from the group consisting of N, O andS; wherein each of 6- to 10-membered aromatic carbocycle, heteroaryl orheterocyclyl is unsubstituted or substituted with one or more groups asdescribed herein.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring A is 6- to 10-membered aromaticcarbocycle.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring A is phenyl; wherein phenyl isunsubstituted or substituted with one or more groups as describedherein.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring A is a 5- or 6-membered heteroarylcontaining 1, 2 or 3 heteroatoms independently selected from the groupconsisting of N, O and S; wherein the heteroaryl group is unsubstitutedor substituted with one or more groups as described herein.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring A is 5- or 6-membered heteroarylselected from the group consisting of pyrrole, pyrazole, imidazole,pyrazine, furan, thiophene, oxazole, oxadiazole, thiazole, thiadiazole,pyridine, pyrimidine, and tetrazole; wherein each of the heteroaryl isunsubstituted or substituted with one or more groups as describedherein.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring A is pyridine, thiophene,thiazole, thiadiazole or pyrimidine; wherein each of pyridine,thiophene, thiadiazole, thiazole and pyrimidine is unsubstituted orsubstituted with one or more groups as described herein.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring A is pyridine, thiophene orthiazole; wherein each of pyridine, thiophene and thiazole isunsubstituted or substituted with one or more groups as describedherein.

According to one embodiment, the present invention encompasses acompound of Formula (I); wherein Ring B is (C₆-C₁₀)aryl; wherein(C₆-C₁₀)aryl is unsubstituted or substituted with one or more groups asdescribed herein.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring B is phenyl; wherein said phenylis unsubstituted or substituted with one or more R³ groups as describedherein.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring B is unsubstituted phenyl.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring B is phenyl which is substitutedwith one to three R³ groups; wherein R³ group at each occurrence isindependently selected from the group consisting of hydrogen, halogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,heteroaryl and heterocyclyl.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring B is phenyl which is substitutedwith one R³ selected from the group consisting of hydrogen, halogen,(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl and heterocyclyl.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring B is phenyl which is unsubstitutedor substituted with halogen.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring B is phenyl which is unsubstitutedor substituted with fluoro.

According to one embodiment, the present invention encompasses acompound of Formula (I); wherein Ring B is 6- to 10-membered heteroarylwhich contains 1, 2 or 3 heteroatoms independently selected from N, Oand S.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring B is a 6-membered heteroaryl whichcontains 1, 2 or 3 N; wherein said heteroaryl is unsubstituted orsubstituted with one or more groups as described herein.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring B is selected from the groupconsisting of pyridine, pyridazine, pyrimidine, pyrazine,1,2,3-triazine, 1,2,4-triazine and 1,3,5-triazine; which areunsubstituted or substituted with one or more groups as describedherein.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring B is pyridine; which isunsubstituted or substituted with one or more groups as describedherein.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring B is pyridine which isunsubstituted or substituted with one R³ selected from the groupconsisting of hydrogen, halogen, (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl andheterocyclyl.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring B is pyridine which isunsubstituted or substituted with heterocyclyl.

According to one embodiment, the present invention encompasses acompound of Formula (I); wherein Ring B is (C₆-C₁₀)aryl; or 6- to10-membered heteroaryl which contains 1, 2 or 3 heteroatomsindependently selected from N, O and S; and X is —(CR⁸R⁹)_(p)—O—,—(CR⁸R⁹)_(p)—S— or —(CR⁸R⁹)_(p)—N(R¹⁰)—; wherein R⁸, R⁹ and p are asdefined above.

According to one embodiment, the present invention encompasses acompound of Formula (I); wherein: Ring C is 6- to 10-membered heteroarylwhich contains 1, 2 or 3 heteroatoms independently selected from N, Oand S.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring C is a 6-membered heteroaryl whichcontains 1, 2 or 3 N; wherein said heteroaryl is unsubstituted orsubstituted with one or more groups as described herein.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring C is selected from the groupconsisting of pyridine, pyridazine, pyrimidine, pyrazine,1,2,3-triazine, 1,2,4-triazine and 1,3,5-triazine; which areunsubstituted or substituted with one or more groups as describedherein.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring C is pyridine; which isunsubstituted or substituted with one or more groups as describedherein.

According to one embodiment, the present invention encompasses acompound of Formula (I); wherein Ring C is (C₆-C₁₀)aryl; wherein(C₆-C₁₀) aryl is unsubstituted or substituted with one or more R⁴ groupsas described herein.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring C is phenyl; wherein said phenylis unsubstituted or substituted with one or more R⁴ groups as describedherein.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring C is phenyl and R⁴ is hydrogen.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring C is phenyl which is substitutedwith one to three R⁴ groups; wherein R⁴ group at each occurrence isindependently selected from the group consisting of hydrogen, halogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, halogen, cyano,—NR¹⁰R¹¹, —S(O)_(t)R¹² and —C(O)R¹³; wherein R¹⁰, R¹¹, R¹², R¹³ and tare as defined above.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring C is (C₆-C₁₀)aryl; or 6- to10-membered heteroaryl which contains 1, 2 or 3 heteroatomsindependently selected from the group consisting of N, O and S; Y is—(CR¹⁴R¹⁵)_(g)—; where R¹⁴, R¹⁵ and g are as defined; and Q is —CO₂M or—CONH₂, where M is hydrogen, deuterium or (C₁-C₆)alkyl.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring C is (C₆-C₁₀)aryl; which isunsubstituted or substituted with one or more groups as describedherein; and Y is —(CR¹⁴R¹⁵)_(g); wherein R¹⁴ and R¹⁵ are independentlyselected from hydrogen and (C₁-C₆)alkyl and g is as defined above; and Qis —CO₂M; where M is H or (C₁-C₆)alkyl.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring C is (C₆-C₁₀)aryl; which isunsubstituted or substituted with one or more groups as describedherein; and Y is —(CR¹⁴R¹⁵)_(g); wherein R¹⁴ and R¹⁵ are combinedtogether to form a 3- to 5-membered saturated carbocycle or 4- to6-membered saturated heterocycle which optionally contains 1 or 2heteroatoms independently selected from the group consisting of N, O andS; wherein said ring is unsubstituted or substituted with a substituentindependently selected from the group consisting of (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, halogen, cyano, (C₆-C₁₀)aryl,heteroaryl and heterocyclyl; and Q is —CO₂M; where M is H or(C₁-C₆)alkyl.

According to another embodiment, the present invention encompasses acompound of Formula (I), wherein X is —(CR⁸R⁹)_(p)—O—, wherein R⁸, R⁹and p are as defined above.

According to another embodiment, the present invention encompasses acompound of Formula (I), wherein Y is —(CR¹⁴R¹⁵)_(g)—; wherein R¹⁴ andR¹⁵ are independently hydrogen or (C₁-C₆)alkyl.

According to another embodiment, the present invention encompasses acompound of Formula (I), wherein Y is —(CR¹⁴R¹⁵)_(g)—; wherein R¹⁴ andR¹⁵ are hydrogen.

According to another embodiment, the present invention encompasses acompound of Formula (I), wherein Y is —(CR¹⁴R¹⁵)_(g)—; wherein R¹⁴ andR¹⁵ are hydrogen, and g is 2, 3 or 4.

According to another embodiment, the present invention encompasses acompound of Formula (I), wherein Y is —(CR¹⁴R¹⁵)_(g)—; wherein R¹⁴ andR¹⁵ are hydrogen, and g is 3.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Q is —CO₂M, wherein M is hydrogen,deuterium or (C₁-C₆)alkyl.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Q is —CO₂M, wherein M is hydrogen.

According to an embodiment, the present invention encompasses a compoundof Formula (I), wherein Ring B is represented as follows;

which can be selected from phenyl or a 6-membered heteroaryl; whereineach of the phenyl and heteroaryl is unsubstituted or substituted withone or more groups as described herein.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring B is attached to Ring A in1,2-disubstituted fashion with respect to variable X and is representedby the following structural formula:

wherein,

-   is point of attachment of X with Ring C.-   Ring A, ring B, R₁, R₂, R₃, X and m are as defined above.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein Ring B and Ring A are bonded to formthe group selected from

wherein,

-   is point of attachment of X with Ring C.-   Ring B, R₁, R₂, R₃, X and m are as defined above.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein R₁ is

wherein

-   R⁵ is hydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy, cyano,    —NR¹⁰R¹¹, —CONR¹⁰R¹¹, (C₁-C₆)alkoxy, halo(C₁-C₆)alkylene or    —C(O)R¹³;-   R⁶ and R⁷ are independently selected from the group consisting of    hydrogen, (C₁-C₆)alkyl and halogen;-   is point of attachment of R¹ with Ring A;-   J is —CH₂—, —CHF—, —CF₂—, —O—, —NR^(a)— or —S—;-   “-----” is an optional bond;-   R^(a) is hydrogen or (C₁-C₆)alkyl;-   r is 0, 1 or 2.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein R¹ is

wherein

R₅ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, cyano, —NR¹⁰R¹¹,or halo(C₁-C₆)alkyl;

J is —CH₂ or —O—;

-   R⁶ and R⁷ are independently selected from the group consisting of    hydrogen and (C₁-C₆)alkyl; r is 1; and R₂ is hydrogen, halogen,    (C₁-C₆)alkyl or cyano.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein R¹ and R² are combined together withone or two atoms of Ring A to form:

-   i) 4- to 6-membered saturated carbocycle or-   ii) 5- to 6-membered saturated heterocycle which contains 1, 2 or 3    heteroatoms independently selected from the group consisting of N, O    and S; wherein said ring is unsubstituted or substituted with one or    more groups independently selected from the group consisting of    (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, halogen,    cyano, (C₆-C₁₀)aryl, heteroaryl and heterocyclyl.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein R¹ and R² are combined together withone or two atoms of Ring A to form the following groups;

wherein the groups are unsubstituted or substituted with one or moregroups independently selected from the group consisting of(C₁-C₆)alkenyl, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy,halogen, cyano, oxo, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heteroaryl andheterocyclyl.

According to one embodiment, the present invention encompasses acompound of Formula (I), wherein the Ring B is represented as

and the Ring C is represented as

Accordingly, in one embodiment the compound of formula I of the presentinvention encompasses a compound of formula Ia;

wherein:

Ring A is saturated or unsaturated 4- to 6-membered carbocycle; or 5- to6-membered heteroaryl; or saturated or partly saturated or unsaturated5- to 10-membered heterocyclic ring which contains 1, 2, 3 or 4heteroatoms independently selected from N, O and S;

Ring B is phenyl; or 6-membered heteroaryl which contains 1, 2 or 3 Natoms;

Ring C is phenyl; or 6-membered heteroaryl which contains 1, 2 or 3 Natoms;

Y is —(CR¹⁴R¹⁵)_(g)—;

Q is —CO₂M, —CONH₂, —CONH[(C₁-C₆)alkyl], —CON[(C₁-C₆)alkyl]₂ or—CONHSO₂(C₁-C₆)alkyl;

M is hydrogen, deuterium or (C₁-C₆)alkyl;

R¹ is

wherein

-   is point of attachment;-   J is —CH₂—, —CHF—, —CF₂—, —CH[(C₁-C₆)alkyl], —C[(C₁-C₆)alkyl]₂, —O—,    —NR^(a)— or —S—;-   “-----” represents an optional bond;

R^(a) is hydrogen, (C₁-C₆)alkyl and halo(C₁-C₆)alkyl;

R² is selected from the group consisting of hydrogen, halogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,heteroaryl, heterocyclyl, (C₆-C₁₀)aryl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C₆-C₁₀)aryl-, heterocyclyl-(C₁-C₆)alkyl-,(C₁-C₆)alkyl-heterocyclyl, heteroaryl-(C₁-C₆)alkyl-,(C₁-C₆)alkyl-heteroaryl-, cyano, —C(O)NR¹⁰R¹¹, —C(S)NR¹⁰R¹¹,—S(O)_(t)R¹² and —C(O)R¹³; or

R¹ and R² are combined together with one or two atoms of Ring A to form:

-   i) a 3- to 8-membered partly saturated or saturated carbocycle; or-   ii) a 3- to 8-membered saturated heterocycle which contains 1, 2 or    3 heteroatoms independently selected from the group consisting of N,    O and S;    wherein the said carbocycle or the heterocycle can be unsubstituted    or substituted with one or more groups independently selected from    the group consisting of (C₁-C₆)alkenyl, (C₁-C₆)alkyl,    halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, halogen, cyano, oxo,    (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heteroaryl and heterocyclyl;

R³, at each occurrence, is independently selected from the groupconsisting of hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heteroaryl, heterocyclyl,(C₆-C₁₀)aryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C₆-C₁₀)aryl,heterocyclyl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heterocyclyl,heteroaryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heteroaryl, cyano, —NR¹⁰R¹¹,—C(O)NR¹⁰R¹¹, —C(S)NR¹⁰R¹¹, —S(O)_(t)R¹² and —C(O)R¹³;

R⁴, at each occurrence, is independently selected from the groupconsisting of hydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, halogen,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heteroaryl, heterocyclyl,(C₆-C₁₀)aryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C₆-C₁₀)aryl,heterocyclyl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heterocyclyl,heteroaryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heteroaryl, cyano, —NR¹⁰R¹¹,—S(O)_(t)R¹² and —C(O)R¹³;

R⁵, at each occurrence, is independently selected from the groupconsisting of hydrogen, (C₁-C₆)alkyl, hydroxy, cyano, —COR¹⁰, —NR¹⁰R¹¹,—CONR¹⁰R¹¹, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, —S(O)_(t)R¹² and —C(O)R¹³;

R⁶ and R⁷ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and halogen;

R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, deuterium, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and halogen;

or

R⁸ and R⁹ can combine together to form

-   i) a 3- to 5-membered saturated carbocycle; or-   ii) a 3- to 5-membered saturated heterocycle which contains 1, 2 or    3 heteroatoms independently selected from the group consisting of N,    O and S;

R¹⁰ is hydrogen, hydroxy, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl,(C₆-C₁₀)aryl-(C₁-C₆)alkylene-, (C₁-C₆)alkyl-(C₆-C₁₀)arylene-,heterocyclyl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heterocyclyl,heteroaryl-(C₁-C₆)alkyl or (C₁-C₆)alkyl-heteroaryl;

R¹¹ is hydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,(C₆-C₁₀)aryl, heterocyclyl, heteroaryl, (C₆-C₁₀)aryl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C₆-C₁₀)aryl, heterocyclyl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-heterocyclyl, heteroaryl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-heteroaryl or —S(O)_(t)R¹²;

or

R¹⁰ and R¹¹ are combined together to form 3- to 8-membered saturated orunsaturated ring which contains 1, 2 or 3 heteroatoms independentlyselected from N, O and S;

R¹² and R¹³ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,(C₆-C₁₀)aryl, heterocyclyl, heteroaryl, (C₆-C₁₀)aryl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C₆-C₁₀)aryl, heterocyclyl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-heterocyclyl, heteroaryl-(C₁-C₆)alkyl and(C₁-C₆)alkyl-heteroaryl;

R¹⁴ and R¹⁵ are independently selected from hydrogen, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl and halogen; or

R¹⁴ and R¹⁵ are combined together to form a 3- to 5-membered saturatedor unsaturated ring which optionally contains 1 or 2 heteroatomsindependently selected from N, O and S;

g is 2, 3, 4, 5 or 6;

m is 0, 1 or 2;

n is 0, 1 or 2;

p is 1, 2 or 3;

r is 0, 1, 2, 3 or 4;

t is 0, 1 or 2;

wherein

(C₁-C₆)alkyl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, heterocyclyl,heteroaryl, amino, cyano, nitro, —NH(C₁-C₆)alkyl, —N[(C₁-C₆)alkyl]₂,—C(O)(C₁-C₆)alkyl, —C(O)O(C₁-C₆)alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl,—C(O)N[(C₁-C₆)alkyl]₂ and —C(O)NHSO₂(C₁-C₆)alkyl;

(C₃-C₁₀)cycloalkyl is unsubstituted or substituted with one or moregroups independently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,amino, cyano and nitro;

carbocycle is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, hydroxy, halogen, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl, heteroaryl, heterocyclyl, amino,cyano, nitro, —C(O)O(C₁-C₆)alkyl, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; whereinR¹⁰, R¹¹, R¹² and t are as defined above;

(C₆-C₁₀)aryl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, amino,cyano, nitro, —C(O)O(C₁-C₆)alkyl, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; whereinR¹⁰, R¹¹, R¹² and t are as defined above;

heterocyclyl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, amino,cyano, nitro, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and tare as defined above;

heteroaryl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,heterocyclyl, heteroaryl, amino, cyano, nitro, —C(O)NR¹⁰R¹¹ or—S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are as defined above;

or a stereoisomer, a tautomer or a geometrical isomer thereof or apharmaceutically acceptable salt, a pharmaceutically acceptable solvate,a prodrug, a polymorph, an N-oxide, a S-oxide or a carboxylic acidisostere thereof.

Representative compounds of Formula (I) encompassed in accordance withthe present invention include:

-   4-(4-((2-(5-(1-Cyanocyclopropyl)thiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   3-(4-((2-(5-(1-Cyanocyclopropyl)thiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)propanoic    acid;-   4-(4-((4-Fluoro-4′-(1-methylcyclopropyl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoic    acid;-   4-(4-((4′-(1-Cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoic    acid;-   3-(4-((4′-(1-Cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoic    acid;-   3-(4-((2-(6-(1-Cyanocyclopropyl)pyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)propanoic    acid;-   4-(4-((4′-Cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoic    acid;-   4-(4-((2-(2,3-Dihydro-1H-inden-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(4-((5-Fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoic    acid;-   4-(4-((2-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(4-((2-(5-Cyclopropylthiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(4-((5-Fluoro-2-(5-(1-hydroxycyclobutyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoic    acid;-   3-(4-((4-Fluoro-4′-(oxetan-3-yl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoic    acid;-   3-(4-((4-Fluoro-4′-(1-hydroxycyclobutyl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoic    acid;-   3-(4-((4′-(5,5-Dimethylcyclopent-1-en-1-yl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoic    acid;-   4-(4-((4′-Cyclohexyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoic    acid;-   3-(4-((5-Fluoro-2-(6-(oxetan-3-yl)pyridin-3-yl)benzyl)oxy)phenyl)propanoic    acid;-   3-(5-((4′-(1-Cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)propanoic    acid;-   4-(4-((4-(4-(1-Cyanocyclopropyl)phenyl)pyridin-3-yl)methoxy)phenyl)butanoic    acid;-   3-(5-((2-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)pyridin-2-yl)propanoic    acid;-   3-(4-((2-(4-(1-Cyanocyclopropyl)phenyl)pyridin-3-yl)methoxy)phenyl)propanoic    acid;-   4-(4-((2-(2,3-Dihydrobenzofuran-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(4-((5-Fluoro-2-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)benzyl)oxy)phenyl)butanoic    acid;-   4-(4-((2-(6,7-Dihydro-5H-cyclopenta[b]pyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(4-((5-Fluoro-2-(7-methylene-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoic    acid;-   4-(4-((2-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)benzyl)oxy)phenyl)butanoic    acid;-   4-(4-((2-(5,6,7,8-Tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoic    acid;-   4-(4-((2-(5-Cyclobutylthiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(4-((4′-Cyclopropyl-4-fluoro-3′-methyl-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoic    acid;-   4-(4-((2-(6-Cyclopropylpyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(4-((2-(2-Cyclopropylpyrimidin-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(4-((2-(4-Cyclopropylthiazol-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(4-((2-(2,3-Dihydro-1H-inden-5-yl)benzyl)oxy)phenyl)butanoic acid;-   4-(4-((5-Fluoro-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoic    acid;-   4-(4-((2-(7,8-Dihydronaphthalen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(4-((5-Fluoro-2-(5-methylene-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoic    acid;-   4-(4-((5-Fluoro-2-(5-methyl-7,8-dihydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoic    acid;-   4-(4-((5-Fluoro-2-(5-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoic    acid;-   4-(4-((5-Fluoro-2-(5-methoxy-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoic    acid;-   4-(4-((5-Fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoic    acid;-   4-(4-((5-Fluoro-2-(5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoic    acid;-   4-(4-((5-Fluoro-2-(5-(1-fluorocyclopropyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoic    acid;-   4-(4-((4′-(2,2-Difluorocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoic    acid;-   4-(4-((2-(5-Cyclopropyl-1,3,4-thiadiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(4-((2-(5-Cyclopropylthiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(4-((5-Fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoic    acid;-   4-(4-((2-(5,6-Dihydro-4H-cyclopenta[d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(4-((2-(6,7-Dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(4-((2-(6,7-Dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(4-((2-(4-Cyclopropylthiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoic    acid;-   4-(5-((5-Fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)pyridin-2-yl)butanoic    acid;-   4-(5-((2-(2,3-Dihydrobenzofuran-5-yl)-5-fluorobenzyl)oxy)pyridin-2-yl)butanoic    acid;-   4-(5-((5-Fluoro-2-(6-methoxypyridin-3-yl)benzyl)oxy)pyridin-2-yl)butanoic    acid;-   4-(5-((4′-Cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)butanoic    acid;-   4-(5-((5-Fluoro-2-(5-methylthiophen-2-yl)benzyl)oxy)pyridin-2-yl)butanoic    acid;-   4-(5-((2-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)pyridine-2-yl)butanoic    acid;-   4-(5-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)butanoic    acid;-   4-(5-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)pyridin-2-yl)butanoic    acid;-   4-(5-((5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzyl)oxy)pyridin-2-yl)butanoic    acid; or-   4-(5-((4-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)pyridin-2-yl)butanoic    acid; and-   4-(5-((2-(5-cyclopropylthiophen-2-yl)-4-fluorobenzyl)oxy)pyridin-2-yl)butanoic    acid    or a stereoisomer, a tautomer or a geometrical isomer thereof; or a    pharmaceutically acceptable salt, a pharmaceutically acceptable    solvate thereof.

The compounds of the present invention include all stereoisomeric andtautomeric forms and mixtures thereof in all ratios and theirpharmaceutically acceptable salts, solvates, prodrugs, polymorphs,N-oxides, S-oxides and carboxylic acid isosteres.

According to another aspect of the present invention, there are providedprocesses for the preparation of the compounds of formula (I) orpharmaceutically acceptable salts thereof.

Thus, the compounds of formula (I) can be prepared by various methodsincluding using methods well known to a person skilled in the art.Examples of processes for the preparation of a compound of formula I aredescribed below and illustrated in the following scheme but are notlimited thereto. It will be appreciated by persons skilled in the artthat within certain of the processes described herein, the order of thesynthetic steps employed may be varied and will depend inter alia onfactors such as the nature of functional groups present in a particularsubstrate and the protecting group strategy (if any) to be adopted.Clearly, such factors will also influence the choice of reagent such asbases, solvents, coupling agents to be used in the reaction steps.

The reagents, reactants and intermediates used in the followingprocesses are either commercially available or can be prepared accordingto standard procedures known in the art, for instance those reported inthe literature references.

In the following scheme and the description of general procedures forthe preparation of the compounds of formula (I), for ease of referencethe starting compounds and the intermediates used for the synthesis ofthe compounds of the present invention, are designated as compounds 1,2, 3, 4, 5a, 5b and 6 respectively. In the following scheme generalprocedure followed for the synthesis of the compounds of formula (I) arereferred to as procedure A, B, C and D respectively, for ease ofreference.

Thus, the general procedure followed for the preparation of thecompounds of formula I is depicted in the following Scheme-1 andScheme-2.

General Procedure A:

A mixture of compound 1 (wherein ring B, R³ and m are as defined),compound 2 (wherein ring C, R⁴, n and Y are as defined and R is methylor ethyl), cesium carbonate and anhydrous dimethylfomamide (DMF) arestirred at room temperature for 3 h. The reaction mixture is quenchedwith ice cold water and extracted with ethyl acetate. The obtainedorganic layer is washed with a brine solution, dried over sodiumsulphate, concentrated and purified by flash chromatography to obtaincompound 3 (wherein ring B, ring C, R³, R⁴, m, n and Y are as definedand R is methyl or ethyl).

General Procedure B:

A mixture of the compound 3 as obtained from general Procedure A,bispinacolato diborane [commercially available], potassium acetate,[PdCl₂(dppf)]CH₂Cl₂ [commercially available] and 1,4-dioxane is taken ina round bottom flask and purged with argon for 15-20 mins. The resultingreaction mixture was heated to 80° C. overnight, then cooled to roomtemperature and filtered over Celite®. The filtrate is concentrated andthe residue is dissolved in ethyl acetate. The organic layer is washedwith water and with brine solution, dried over sodium sulphate,concentrated and purified by flash chromatography to obtain compound 4(wherein ring B, ring C, R³, R⁴, m, n and Y are as defined and R ismethyl or ethyl).

General Procedure C

A mixture of compound 5a (wherein ring A, R¹ and R² are as defined), thecompound 4 as obtained from general Procedure B, potassium carbonate, amixture of solvents such as 1,4-dioxane and water is taken in roundbottom flask and purged with argon for about 5 mins. Then,tetrakis(triphenylphosphine)palladium(0) [commercially available] isadded and purged with argon for about another 5 mins. The resultingreaction mixture is heated to 80° C. overnight, then cooled to roomtemperature and filtered over Celite®. The filtrate is concentrated andthe residue is dissolved in ethyl acetate. The solution is washed withwater and brine solution, dried over sodium sulphate, concentrated andpurified by flash chromatography to obtain the compound of formula (I)(wherein ring A, ring B, ring C, R¹, R², R³, R⁴, m, n and Y are asdefined and R is methyl or ethyl). The compound of formula (I) (whereinring A, ring B, ring C, R¹, R², R³, R⁴, m, n and Y are as defined and Ris methyl or ethyl) can also be produced from the compound 3 (obtainedfrom general Procedure A) by direct treatment with compound 5b (whereinring A, R¹ and R² are as defined), under similar reaction conditions.

General Procedure D

The compound of formula (I) (wherein ring A, ring B, ring C, R¹, R², R³,R⁴, m, n and Y are as defined and R is methyl or ethyl) obtained fromgeneral Procedure C is dissolved in tetrahydrofuran (THF) and methanoland then LiOH.H₂O (5 eqv.) in water (2 mL/mM) is added. The resultingreaction mixture is stirred at room temperature for 3 h. The reactionmixture is concentrated in vacuo, acidified with 1N HCl solution andextracted with ethyl acetate. The combined organic layer is washed withbrine, dried over sodium sulphate and concentrated under vacuum toobtain compound of formula (I) (wherein ring A, ring B, ring C, R¹, R²,R³, R⁴, m, n and Y are as defined and R is hydrogen).

General Procedure E:

A mixture of benzyl bromide, compound 7 (wherein ring C, R⁴ and n are asdefined), cesium carbonate and acetonitrile are stirred at roomtemperature for 3 h. The reaction mixture is filtered and washed withethyl acetate. The combined organic layers are dried over sodiumsulphate, concentrated to obtain compound 8 (wherein ring C, R⁴ and nare as defined).

General Procedure F:

A mixture of the compound 8 as obtained from general Procedure E isstirred in dry THF under argon atmosphere. (4-Ethoxy-4-oxobutyl)zinc(II)bromide in THF is added followed by addition of Pepsi-iPr catalyst. Theresulting reaction mixture is stirred overnight at RT. The reactionmixture is decomposed with saturated solution of ammonium chloride andthen extracted with ethyl acetate. The organic layer is washed withbrine solution, dried over sodium sulphate, concentrated and purified bycolumn chromatography to obtain compound 9 (wherein ring C, R⁴, n and Yare as defined and R is methyl or ethyl).

General Procedure G:

Compound 9 (wherein ring C, R⁴, n and Y are as defined and R is methylor ethyl), obtained from general Procedure F is stirred in dry ethanol.The reaction mixture is set for hydrogenation at 40 psi for 3 h inpresence of palladium on carbon (10%) catalyst. The reaction mixture wasfiltered and concentrated to obtain the compound 10 (wherein ring C, R⁴,n and Y are as defined and R is methyl or ethyl).

General Procedure H:

The compound 9 as obtained from general Procedure G and compound 11(wherein R³ and m are as defined) is stirred in acetonitrile. Cesiumcarbonate is added and reaction mixture is stirred overnight. Theresulting reaction mixture is filtered and the residue is washed withethyl acetate. The combined organic layers are concentrated and purifiedby flash column chromatography to obtain compound 12 (wherein ring B,ring C, R³, R⁴, m, n and Y are as defined and R is methyl or ethyl).

General Procedure I:

The compound 12 as obtained from general Procedure H, compound 13(wherein ring A, R¹ and R² are as defined) and potassium carbonate isstirred in dioxane:water (4:1) mixture and purged with argon for 5minutes. Palladium tetrakis is added and reaction mixture is stirred at111° C. for 5 h. The resulting reaction mixture is diluted with ethylacetate filtered through Celite®, concentrated and purified by flashcolumn chromatography to obtain compound of formula (I) (wherein ring A,ring B, ring C, R¹, R², R³, R⁴, m, n and Y are as defined and R ismethyl or ethyl).

General Procedure J:

The compound of formula (I) (wherein ring A, ring B, ring C, R¹, R², R³,R⁴, m, n and Y are as defined and R is methyl or ethyl) obtained fromgeneral Procedure I is dissolved in tetrahydrofuran (THF) and methanoland then LiOH.H₂O (5 eqv.) in water (2 mL/mM) is added. The resultingreaction mixture is stirred at room temperature for 3 h. The reactionmixture is concentrated in vacuo, acidified with 1N HCl solution andextracted with ethyl acetate. The combined organic layer is washed withbrine, dried over sodium sulphate and concentrated under vacuum toobtain compound of formula (I) (wherein ring A, ring B, ring C, R¹, R²,R³, R⁴, m, n and Y are as defined and R is hydrogen).

The compounds of formula (I) can be converted into theirpharmaceutically acceptable salts by following procedure known topersons skilled in the art.

The pharmaceutically acceptable salt of the compounds of Formula (I) areprepared with relatively non-toxic acids or bases, depending on theparticular substituents found on the compound described herein. When thecompounds of Formula (I) of the present invention contain an acidicgroup they can form an addition salt with a suitable base. For example,pharmaceutically acceptable base addition salts of the compounds of thepresent invention may include their alkali metal salts such as sodium,potassium, calcium, magnesium, ammonium or an organic base additionsalt. Examples of pharmaceutically acceptable organic base additionsalts of the compounds of the present invention include those derivedfrom organic bases like lysine, arginine, guanidine, diethanolamine,metformin or other organic bases known to the person skilled in the art.

When the compounds of Formula (I) of the present invention contain oneor more basic groups, they can form an addition salt with an inorganicor an organic acid. Examples of pharmaceutically acceptable acidaddition salts include those derived from inorganic acids like boricacid, perchloric acid, hydrochloric acid, hydrobromic acid, hydrofluoricacid, hydriodic acid, nitric acid, carbonic acid, monohydrogencarbonicacid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoricacid, monohydrogensulfuric acid, sulfuric acid, phosphorous acids orother inorganic acids known to the person skilled in the art.Furthermore, examples of pharmaceutically acceptable acid addition saltsinclude the salts derived from organic acids such as acetic acid,propionic acid, isobutyric acid, oxalic acid, malic acid, tartaric acid,citric acid, ascorbic, maleic acid, malonic acid, benzoic acid, succinicacid, suberic acid, fumaric acid, mandelic acid, phthalic acid,benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid,glucuronic acid, galacturonic acid, naphthoic acid, camphoric acid orother organic acids known to the person skilled in the art. Certainspecific compounds of the present invention contain both basic andacidic functionalities that allow the compounds to be converted intoeither base or acid addition salts.

The pharmaceutically acceptable salts of the present invention can besynthesized from the subject compound i.e. the compound of Formula (I)which contains a basic or acidic moiety by conventional chemicalmethods. Generally the salts are prepared by contacting the free base oracid with desired salt-forming inorganic or organic acid or a base in asuitable solvent or dispersant or by anion exchange or cation exchangewith other salts. Suitable solvents are, for example, ethyl acetate,ethers, alcohols, acetone, or mixtures of these solvents.

Those skilled in the art will recognize that the compounds of Formula(I) of the present invention contain asymmetric or chiral centers, andtherefore exist in different stereoisomeric forms, as racemic mixturesof enantiomers, mixtures of diastereomers or enantiomerically oroptically pure compounds. The term “chiral” refers to molecules whichhave the property of non-superimposability of the mirror image cohort,while the term “achiral” refers to molecules which are superimposable ontheir mirror image partner. It is intended that all stereoisomeric formsof the compounds of the invention, including but not limited to,diastereomers and enantiomers, as well as mixtures thereof such asracemic mixtures, geometric isomers form part of the present invention.

When the compounds of Formula (I) of the present invention contain onechiral center, the compounds exist in two enantiomeric forms and thepresent invention includes both enantiomers and mixtures of enantiomers,such as the specific 50:50 mixture referred to as a racemic mixtures.The enantiomers can be resolved by methods known to those skilled in theart, such as formation of diastereoisomeric salts which may beseparated, for example, by crystallization (see, CRC Handbook of OpticalResolutions via Diastereomeric Salt Formation by David Kozma (CRC Press,2001)); formation of diastereoisomeric derivatives or complexes whichmay be separated, for example, by crystallization, gas-liquid or liquidchromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic esterification; orgas-liquid or liquid chromatography in a chiral environment, for exampleon a chiral support for example silica with a bound chiral ligand or inthe presence of a chiral solvent. It will be appreciated that where thedesired enantiomer is converted into another chemical entity by one ofthe separation procedures described above, a further step is required toliberate the desired enantiomeric form. Alternatively, specificenantiomers may be synthesized by asymmetric synthesis using opticallyactive reagents, substrates, catalysts or solvents, or by converting oneenantiomer into the other by asymmetric transformation. Designation of aspecific absolute configuration at a chiral carbon of the compounds ofthe invention is understood to mean that the designated enantiomericform of the compounds is in enantiomeric excess (ee) or in other wordsis substantially free from the other enantiomer. For example, the “R”forms of the compounds are substantially free from the “S” forms of thecompounds and are, thus, in enantiomeric excess of the “S” forms.Conversely, “S” forms of the compounds are substantially free of “R”forms of the compounds and are, thus, in enantiomeric excess of the “R”forms. Enantiomeric excess, as used herein, is the presence of aparticular enantiomer at greater than 50%. In a particular embodimentwhen a specific absolute configuration is designated, the enantiomericexcess of depicted compounds is at least about 90%. When a compound ofFormula (I) of the present invention has two or more chiral carbons itcan have more than two optical isomers and can exist indiastereoisomeric forms. For example, when there are two chiral carbons,the compound can have up to 4 optical isomers and 2 pairs of enantiomers((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g.,(S,S)/(R,R)) are mirror image stereoisomers of one another. Thestereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) arediastereomers. The diastereoisomeric pairs may be separated by methodsknown to those skilled in the art, for example chromatography orcrystallization and the individual enantiomers within each pair may beseparated as described above. The present invention includes eachdiastereoisomer of such compounds and mixtures thereof.

The isotopically labeled forms of compounds of Formula (I), can beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described above or in the subsequentsection on examples by using a corresponding isotopically labeledreagent in place of the non-labeled reagent.

In one embodiment, the compounds of Formula (I) exists as tautomers, andit is intended to encompass all the tautomeric forms of the compoundswithin the scope of the present invention.

The present invention furthermore includes all the solvates of thecompounds of Formula (I), for example, hydrates and the solvates formedwith other solvents of crystallisation, selected from alcohols such asmethanol, ethanol, 1-propanol or 2-propanol, ethers such as diethylether, isopropyl ether or tetrahydrofuran, esters such as methyl acetateor ethyl acetate, ketone such as acetone or their mixtures thereof.Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms.

It is further intended to encompass various polymorphs of compounds ofFormula (I) within the scope of the present invention. Variouspolymorphs of compounds of the present invention can be prepared bystandard crystallisation procedures known in the art. Thecrystallisation technique employed can utilize various solvents or theirmixtures, temperature conditions and various modes of cooling, rangingfrom very fast to very slow cooling. The presence of polymorphs can bedetermined by IR (Infra-red) spectroscopy, solid probe NMR (NuclearMagnetic Resonance) spectroscopy, differential scanning calorimetry,powder X-ray diffraction or such other standard techniques.

Furthermore, the present invention also includes prodrugs of thecompounds of Formula (I). The prodrugs of the compounds of the presentinvention are derivatives of the aforesaid compounds of the inventionwhich upon administration to a subject in need thereof undergoeschemical conversion by metabolic or chemical processes to release theparent drug in vivo from which the prodrug is derived. The preferredprodrugs are pharmaceutically acceptable ester derivatives e.g., alkylesters, cycloalkyl esters, alkenyl esters, benzyl esters, mono- ordi-substituted alkyl esters convertible by solvolysis underphysiological conditions to the parent carboxylic acid, and thoseconventionally used in the art.

The present invention further relates to carboxylic acid isosteres ofthe compounds of Formula (I).

The present invention also relates to N-oxide derivatives of thecompounds of Formula (I).

The present invention also relates to S-oxide derivatives of thecompounds of Formula (I).

In one aspect of the present invention, i.e. the compounds of Formula(I) are GPR120 agonists.

In an embodiment of the present invention, the compounds of Formula (I)find use in the treatment or prophylaxis of a disease or a disordermediated by GPR120.

In another aspect, the present invention relates to a method for thetreatment or prophylaxis of a disease or a disorder mediated by GPR120,comprising administering to a subject in need thereof, a therapeuticallyeffective amount of a compound of Formula (I) or a stereoisomer, atautomer or a geometrical isomer thereof or a pharmaceuticallyacceptable salt thereof.

In an embodiment, the present invention relates to use of the compoundof Formula (I) or a stereoisomer or a tautomer or a pharmaceuticallyacceptable salt thereof for the treatment or prophylaxis of a disease ora disorder mediated by GPR120.

According to one embodiment, the present invention relates to use of thecompounds of Formula (I) or a stereoisomer or a tautomer or apharmaceutically acceptable salt thereof; in the manufacture of amedicament for the treatment or prophylaxis of a disease or a disordermediated by GPR120.

As used herein, the term “a disease or a disorder mediated by GPR120” or“GPR120 mediated disease(s) or condition(s)” refers to a disease or adisorder or a condition characterized by inappropriate, for example,less than or greater than normal, GPR120 activity. A GPR120-mediateddisease or disorder may be completely or partially mediated byinappropriate GPR120 activity.

In an embodiment of the invention, the disease or condition mediated byGPR120 is selected from the group consisting of diabetes, obesity,hyperglycemia, glucose intolerance, insulin resistance,hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, cardiovascular disease,atherosclerosis, kidney disease, polycystic ovary syndrome,ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy,diabetic retinopathy, sexual dysfunction, fatty liver development,dermatopathy, dyspepsia, hypoglycemia, cancer, edema and a disorderrelated to glucose levels such as pancreatic beta cell regeneration.

In an embodiment of the invention, the disease or condition mediated byGPR120 is selected from the group consisting of diabetes, obesity,insulin resistance, hyperglycemia, glucose intolerance,hypercholesterolemia, hypertriglylceridemia, dyslipidemia,hyperlipoproteinemia, hyperinsulinemia, atherosclerosis, diabeticneuropathy, diabetic retinopathy, metabolic syndrome, hypertension andpancreatic beta cell degeneration.

In an embodiment of the invention, the disease or condition mediated byGPR120 is selected from the group consisting of diabetes, obesity,insulin resistance, hyperglycemia, glucose intolerance, metabolicsyndrome and pancreatic beta cell degeneration.

In an embodiment, diabetes is Type 2 diabetes.

In an embodiment, the disease or disorder mediated by GPR120 is ametabolic disorder which refers to one or more diseases or conditions asidentified above.

In an embodiment, the disease or disorder mediated by GPR120 is aninflammatory disorder.

Accordingly, the present invention relates to a method for the treatmentor prophylaxis of a metabolic disorder, comprising administering to asubject in need thereof a therapeutically amount of a compound ofFormula (I) or a stereoisomer or a tautomer or a pharmaceuticallyacceptable salt thereof.

In an embodiment, the present invention provides use of the compound ofFormula (I) or a stereoisomer or a tautomer or a pharmaceuticallyacceptable salt thereof for the treatment or prophylaxis of a metabolicdisorder.

According to one embodiment, the present invention relates to use of thecompounds of Formula (I) or pharmaceutically acceptable salts thereof inthe manufacture of a medicament, for the treatment or prophylaxis of ametabolic disorder.

The term “metabolic disorder” as used herein refers a disorder relatingto abnormality of metabolism. Accordingly, in the context of the presentinvention all the disorders relating to abnormality of metabolism areencompassed in the term “metabolic disorders”.

In one embodiment, the metabolic disorder is selected from the groupconsisting of diabetes, obesity, cardiovascular disease, hypertension,ketoacidosis, insulin resistance, glucose intolerance, hyperglycemia,hypertriglylceridemia, polycystic ovary syndrome, hypercholesterolemia,hyperlipoproteinemia, dyslipidemia, metabolic syndrome, hyperlipidemia,diabetic neuropathy, diabetic retinopathy, edema and related disordersassociated with abnormal plasma lipoprotein, triglycerides andpancreatic beta cell degeneration.

The term “diabetes mellitus” or “diabetes” refers to a chronic diseaseor condition, which occurs when the pancreas does not produce enoughinsulin, or when the body cannot effectively use the insulin itproduces. This leads to an increased concentration of glucose in theblood (hyperglycaemia). Two major forms of diabetes are Type 1 diabetes(Insulin-dependent diabetes mellitus) and Type 2 diabetes (Non-insulindependent diabetes mellitus (NIDDM)). Type 1 diabetes is an autoimmunecondition in which the insulin-producing β-cells of the pancreas aredestroyed which generally results in an absolute deficiency of insulin,the hormone that regulates glucose utilization. Type 2 diabetes oftenoccurs in the face of normal or even elevated levels of insulin and canresult from the inability of tissues to respond appropriately toinsulin. Other categories of diabetes include gestational diabetes (astate of hyperglycemia which develops during pregnancy) and “other”rarer causes (genetic syndromes, acquired processes such aspancreatitis, diseases such as cystic fibrosis, exposure to certaindrugs, viruses, and unknown causes). In an embodiment, diabetes refersto Type 2 diabetes.

The term “metabolic syndrome” refers to a cluster of metabolicabnormalities including abdominal obesity, insulin resistance, glucoseintolerance, diabetes, hypertension and dyslipidemia. Theseabnormalities are known to be associated with an increased risk ofvascular events.

The term “cardiovascular disease” as used herein refers to any diseaseof the heart or blood vessels. One or more diseases of heart encompassedin the term “cardiovascular disease” is selected from, but not limitedto, angina, arrhythmia, coronary artery disease (CAD), cardiomyopathy,myocardial infarction, heart failure, hypertrophic cardiomyopathy,mitral regurgitation, mitral valve prolapse, pulmonary stenosis, etc.The blood vessel disease encompassed in the term “cardiovasculardiseases”, is selected from, but not limited to, for example, peripheralvascular disease, artery disease, carotid artery disease, deep veinthrombosis, venous diseases, atherosclerosis and the like.

In an embodiment, the metabolic disorder is selected from the groupconsisting of diabetes, obesity, insulin resistance, hyperglycemia,glucose intolerance, hypercholesterolemia, hypertriglylceridemia,dyslipidemia, hyperlipoproteinemia, hyperinsulinemia, atherosclerosis,diabetic neuropathy, diabetic retinopathy, metabolic syndrome,hypertension and pancreatic beta cell degeneration.

In an embodiment, the metabolic disorder is selected from the groupconsisting of diabetes, obesity, insulin resistance, glucoseintolerance, dyslipidemia, hyperinsulinemia, metabolic syndrome andpancreatic beta cell degeneration.

In an embodiment, the metabolic disorder is Type 2 diabetes.

Pharmaceutical Compositions

The present invention furthermore relates to pharmaceutical compositionsthat contain a therapeutically effective amount of at least one compoundof Formula (I) or its pharmaceutically acceptable salt in addition to acustomary pharmaceutically acceptable carrier, and to a process for theproduction of a pharmaceutical composition, which includes bringing atleast one compound of Formula (I), into a suitable administration formusing a pharmaceutically suitable and physiologically tolerableexcipient and, if appropriate, further suitable active compounds,additives or auxiliaries.

According to one embodiment, the present invention relates to apharmaceutical composition comprising the compounds of Formula (I) orpharmaceutically acceptable salts thereof and one or morepharmaceutically acceptable excipients; for use as GPR120 agonists andin the treatment or prophylaxis of a disease or a condition mediated byGPR120.

The term “pharmaceutically acceptable carrier” as used herein means anon-toxic, inert, solid, semi-solid, diluent, encapsulating material orformulation auxiliary of any type. Some examples of materials which canserve as pharmaceutically acceptable carriers are sugars such aslactose, glucose, and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; malt; gelatin; talc;as well as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents;preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

It is further intended to include within the scope of the presentinvention the use of the compounds of Formula (I) or itspharmaceutically acceptable salts thereof in combination with at leastone therapeutically active agent.

According to one embodiment, the present invention provides apharmaceutical composition, comprising a therapeutically effectiveamount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof and at least one further therapeutically active agent,together with a pharmaceutically acceptable carrier.

In an embodiment, the present invention relates to use of the compoundof Formula (I) or a pharmaceutically acceptable salt thereof; incombination with a further therapeutically active compound, in thetreatment or prophylaxis of a disease or a condition mediated by GPR120.

The therapeutically active agent used in combination with one or more ofthe compounds of Formula (I) can be selected from the compounds oractive substances known to be used in the treatment of diabetes andother conditions such as obesity, insulin resistance, hyperglycemia,glucose intolerance, hypercholesterolemia, hypertriglylceridemia,dyslipidemia, hyperlipoproteinemia, hyperinsulinemia or atherosclerosis.According to the present invention, the therapeutically active agent,used in combination with the compounds of Formula (I) of the presentinvention can be selected from, but not limited to, insulin,sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones,thiazolidinediones, glucosidase inhibitors, inhibitors of glycogenphosphorylase, glucagon antagonists, HMGCoA reductase inhibitor, GLP-1(Glucogen-like peptide-1) agonists, potassium channel openers,inhibitors of dipeptidylpeptidase IV (DPP-IV), diglycerideacyltransferase (DGAT) inhibitor, insulin sensitizers, modulators ofglucose uptake, modulators of glucose transport and modulators ofglucose reabsorption, modulators of the sodium-dependent glucosetransporter 1 or 2 (SGLT1, SGLT2), compounds which alter lipidmetabolism such as antihyperlipidemic active ingredients andantilipidemic active ingredients, PPARgamma agonists and agents withcombined PPARalpha and gamma activity and active ingredients which acton the ATP-dependent potassium channel of the beta cells.

In an embodiment, the compound of Formula (I) can be used in combinationwith a PPAR gamma agonist selected from rosiglitazone, pioglitazone,rivoglitazone and the like.

In an embodiment, the compound of Formula (I) can be used in combinationwith a HMGCoA reductase inhibitor selected from simvastatin,fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin,rosuvastatin and the like.

In an embodiment, the compound of Formula (I) can be used in combinationwith a sulfonylurea selected from tolbutamide, glibenclamide, glipizide,glimepiride and the like.

In another embodiment, the compound of the Formula (I) can be used incombination with a meglitinide selected from repaglinide, nateglinide,mitiglinide and the like.

In another embodiment, the compound of the Formula (I) can be used incombination with GLP-1 agonist selected from exenatide, liraglutide,taspoglutide albiglutide, lixisenatide and the like.

In another embodiment, the compound of the Formula (I) can be used incombination with DPP-IV inhibitor selected from alogliptin, gemigliptin,linagliptin, saxagliptin, sitagliptin, vildagliptin and the like.

Accordingly, in an embodiment the further therapeutically active agentthat can be used in combination with one or more compounds of Formula(I) encompassed in the present invention, can be selected from one ormore of the agents including, but not limited to, insulin,rosiglitazone, pioglitazone, rivoglitazone, simvastatin, fluvastatin,pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin,tolbutamide, glibenclamide, glipizide, glimepiride, repaglinide,nateglinide, mitiglinide, exenatide, liraglutide, taspoglutidealbiglutide, lixisenatide, alogliptin, gemigliptin, linagliptin,saxagliptin, sitagliptin, vildagliptin and the like.

The pharmaceutical compositions according to the present invention areprepared in a manner known and familiar to one skilled in the art.Pharmaceutically acceptable inert inorganic and/or organic carriersand/or additives can be used in addition to the compounds of Formula (I)and/or its pharmaceutically acceptable salts. For the production ofpills, tablets, coated tablets and hard gelatin capsules it is possibleto use, for example, lactose, corn starch or derivatives thereof, gumarabic, magnesia or glucose, etc. Carriers for soft gelatin capsules andsuppositories are, for example, fats, waxes, natural or hardened oils,etc. Suitable carriers for the production of solutions, for exampleinjection solutions, or of emulsions or syrups are, for example, water,physiological sodium chloride solution or alcohols, for example,ethanol, propanol or glycerol, sugar solutions, such as glucosesolutions or mannitol solutions, or a mixture of the various solventswhich have been mentioned.

Further, the pharmaceutical composition of the present invention alsocontains additives such as, for example, fillers, antioxidants,emulsifiers, preservatives, flavours, solubilisers or colourants. Thepharmaceutical composition of the present invention may also contain twoor more compounds of Formula (I) and/or its pharmaceutically acceptablesalts, the pharmaceutical compositions can also contain one or moreother therapeutically or prophylactically active ingredients.

The pharmaceutical compositions normally contain about 1 to 99%, forexample, about 10 to 80%, by weight of the compounds of Formula (I) ortheir pharmaceutically acceptable salts.

The amount of the active ingredient, the compound of Formula (I) or itspharmaceutically acceptable salt in the pharmaceutical compositions can,for example, vary from about 1 to 500 mg. In case of higher body weightof the mammal in need of the treatment, the pharmaceutical compositionmay contain the compound of Formula (I) in an amount ranging from 5 mgto 1000 mg. The desirable dosage of the compounds of Formula (I) can beselected over a wide range. The daily dosage to be administered isselected to achieve the desired therapeutic effect in subjects beingtreated for metabolic disorders. A dosage of about 0.05 to 50 mg/kg/dayof the compounds of Formula (I) or its pharmaceutically acceptable saltmay be administered. In case of higher body weight of the mammal in needof the treatment, a dosage of about 0.1 to 100 mg/kg/day of the compoundof Formula (I) or its pharmaceutically acceptable salt may beadministered. If required, higher or lower daily dosages can also beadministered. Actual dosage levels of the active ingredients in thepharmaceutical composition of this present invention can be varied so asto obtain an amount of the active ingredient, which is effective toachieve the desired therapeutic response for a particular patient,composition, and mode of administration without being toxic to thepatient. The selected dosage level can be readily determined by askilled medical practitioner in the light of the relevant circumstances,including the condition (diseases or disorder) to be treated, the chosenroute of administration depending on a number of factors, such as age,weight and physical health and response of the individual patient,pharmacokinetics, severity of the disease and the like, factors known inthe medical art.

The pharmaceutical compositions according to the present invention canbe administered orally, for example in the form of pills, tablets,coated tablets, capsules, granules or elixirs. Administration, however,can also be carried out rectally, for example in the form ofsuppositories, or parenterally, for example intravenously,intramuscularly or subcutaneously, in the form of injectable sterilesolutions or suspensions, or topically, for example in the form ofsolutions or transdermal patches, or in other ways, for example in theform of aerosols or nasal sprays.

It is understood that modifications that do not substantially affect theactivity of the various embodiments of this invention are includedwithin scope of the invention disclosed herein. Accordingly, thefollowing examples are intended to illustrate but not to limit scope ofthe present invention.

The abbreviations and terms that are used herein:

LIST OF ABBREVIATIONS ATP Adenosine triphosphate mM Millimolar DCMDichloromethane min(s) Minute(s) DMF N,N-dimethyl formamide nM NanomolarDMSO Dimethyl sulfoxide nm Nanometer TFA Trifluoroacetic acid μlMicrolitre NaOH Sodium hydroxide ml Millilitre EtOH Ethanol μMMicromolar PTSA p-Toluenesulfonic acid pM Picomolar eqv Equivalent NaHSodium hydride g gram NaHCO₃ Sodium bicarbonate h Hour(s) Na₂CO₃ Sodiumcarbonate HCl Hydrochloric acid Na₂SO₄ Sodium sulfate IPA Isopropylalcohol NH₄Cl Ammonium chloride K₂CO₃ Potassium carbonate THFTetrahydrofuran l litre PET Petroleum Ether LiOH•H₂O Lithium hydroxidePPh₃ Triphenylphosphine monohydrate Tris HCl Tris Hydrochloride MeOHMethanol DMF•DMA N,N-dimethyl formamide dimethyl acetal TLC Thin LayerChromatography PdCl₂(dppf)- [1,1′-Bis(diphenylphosphino)ferro- CH₂Cl₂cene]dichloropalladium(II), complex with dichloromethane DASTDiethylaminosulfur trifluoride POCl₃ Phosphorous trichloride MeMgBrMethylmagnesium bromide RT Room temperature (20° C.-25° C.)

Example 14-(4-((2-(5-(1-Cyanocyclopropyl)thiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 1a

Synthesis of methyl-4-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)butanoate

According to general procedure A (as described herein above),1-bromo-2-(bromomethyl)-4-fluorobenzene (1 g, 3.73 mM), was coupled withmethyl 4-(4-hydroxyphenyl)butanoate (0.797 g, 4.11 mM), to give thetitle compound, methyl4-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)butanoate. Yield: 1.39 g, 3.65mM, 98%; ¹H NMR (CDCl₃, 500 MHz) δ 7.52-7.58 (m, 1H), 7.20-7.38 (m, 1H),7.13 (d, J=8.5 Hz, 2H), 6.98-6.96 (m, 3H), 5.08 (s, 2H), 3.68 (s, 3H),2.62 (t, J=8 Hz, 2H), 2.34 (t, J=7.5 Hz, 2H), 1.90-2.0 (m, 2H); MS(m/z); 404.2 [M+Na⁺].

Step 1b

Synthesis of methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate

The compound obtained in step 1a, methyl4-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)butanoate (1.5 g, 3.93 mM), wascoupled with bis(pinacolato)diboron (1.49 g, 5.90 mM) in the presence ofpotassium acetate (1.16 g, 11.80 mM), PdCl₂(dppf)-CH₂Cl₂ adduct (0.064g, 0.079 mM) and 1,4-dioxane according to the general procedure B (asdescribed herein above), to give the title compound, methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate.Yield: 1.6 g, 3.74 mM, 95%; ¹H NMR (CDCl₃, 500 MHz) δ: 7.85 (t, J=7 Hz,1H), 7.31 (d, J=10 Hz, 1H), 7.10 (d, J=8.5 Hz, 2H), 6.99 (m, 1H), 6.91(d, J=8 Hz, 2H), 5.35 (s, 2H), 3.68 (s, 3H), 2.61 (t, J=7.5 Hz, 2H),2.34 (t, J=7.5 Hz, 2H), 1.90-2.0 (m, 2H), 1.30 (m, 12H); MS (m/z) 451.2[M+Na⁺].

Step 1c

Synthesis of methyl4-(4-((2-(5-(1-cyanocyclopropyl)thiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The compound obtained in step 1b, methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(0.150 g, 0.350 mM), was coupled with1-(5-bromothiophen-2-yl)cyclopropanecarbonitrile (0.067 g, 0.292 mM) inthe presence of potassium carbonate (0.121 g, 0.876 mM) 1,4-dioxane (5mL), water (1.25 mL) and tetrakis(triphenylphosphine)palladium(0) (0.017g, 0.015 mM), according to the general procedure C (as described hereinabove), to give the title compound, methyl4-(4-((2-(5-(1-cyanocyclopropyl)thiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate.Yield: 0.109 g, 0.242 mM, 83%; ¹H NMR (CDCl₃, 500 MHz) δ 7.38-7.43 (m,1H), 7.36 (d, J=9.0 Hz, 1H), 7.10 (d, J=8.5 Hz, 2H), 7.05-7.09 (m, 1H),7.02 (d, J=4.0 Hz, 1H), 6.91 (d, J=3.5 Hz, 1H) 6.84 (d, J=8.5 Hz, 2H),5.00 (s, 2H), 3.68 (s, 3H), 2.61 (t, J=7.5 Hz, 2H), 2.34 (t, J=7.5 Hz,2H), 1.59-2.0 (m, 2H), 1.60-1.80 (m, 2H), 1.40-1.50 (m, 2H); MS m/z472.3 [M+Na⁺].

Step 1d

Synthesis of4-(4-((2-(5-(1-Cyanocyclopropyl)thiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Methyl4-(4-((2-(5-(1-cyanocyclopropyl)thiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate(compound obtained in step 1c) (0.095 g, 0.211 mM) was hydrolysed byLiOH:H₂O (0.044 g, 1.057 mM), according to the general procedure D (asdescribed herein above), to give the title compound,4-(4-((2-(5-(1-cyanocyclopropyl)thiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid. Yield: 0.076 g, 0.175 mM, 83%; ¹H NMR (DMSO-d₆, 500 MHz) δ 12.04(s, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.42 (d, J=9.5 Hz, 1H), 7.25-7.35 (m,1H), 7.05-7.15 (m, 4H), 6.88 (d, J=8.5 Hz, 2H), 5.03 (s, 2H), 2.50-2.70(m, 2H), 2.19 (t, J=7.5 Hz, 2H), 1.80-1.85 (m, 2H), 1.70-1.79 (m, 2H),1.48-1.53 (m, 2H); MS (m/z) 458.2 [M+Na⁺].

Example 23-(4-((2-(5-(1-Cyanocyclopropyl)thiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)propanoicacid

Step 2a

Synthesis of ethyl 3-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)propanoate

According to general procedure A (as described herein above),1-bromo-2-(bromomethyl)-4-fluorobenzene (1.517 g, 5.66 mM) was coupledwith ethyl 3-(4-hydroxyphenyl)propanoate (1 g, 5.15 mM), to give thetitle compound, ethyl3-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)propanoate. Yield: 1.6 g, 4.20mM, 82%; ¹H NMR (CDCl₃, 300 MHz) δ 7.50-7.60 (m, 1H), 7.30-7.38 (m, 1H),7.1 (d, J=8.4 Hz, 2H), 6.80-7.00 (m, 3H), 5.07 (s, 2H), 4.13 (q, J=7.2Hz, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.60 (t, J=7.8 Hz, 2H), 1.25 (t, J=7.2Hz, 3H); MS (m/z) 382.3 [M+H^(+]).

Step 2b

Synthesis of ethyl3-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)propanoate

The compound obtained in step 2a, ethyl3-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)propanoate (1.5 g, 3.93 mM),was coupled with bis(pinacolato)diboron (1.499 g, 5.90 mM), potassiumacetate (1.158 g, 11.80 mM), PdCl₂(dppf)-CH₂Cl₂ adduct (0.064 g, 0.079mM) and 1,4-dioxane, according to the general procedure B (as describedherein above), to give the title compound, ethyl3-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)propanoate.Yield: 1.6 g, 3.74 mM, 95%; ¹H NMR (CDCl₃, 300 MHz) δ 7.80-7.90 (m, 1H),7.25-7.35 (m, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.95-7.05 (m, 1H), 6.90 (d,J=8.4 Hz, 2H), 5.35 (s, 2H), 4.13 (q, J=6.9 Hz, 2H), 2.91 (t, J=7.8 Hz,2H), 2.60 (t, J=8.1 Hz, 2H), 1.32 (s, 12H), 1.24 (t, J=7.2 Hz, 3H); MSm/z 429.2 [M+H⁺].

Step 2c

Synthesis of ethyl3-(4-((2-(5-(1-cyanocyclopropyl)thiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)propanoate

The title compound was prepared in an analogous manner as Example 1involving the reaction of ethyl3-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)propanoate(compound of step 2b) (0.150 g, 0.350 mM) with1-(5-bromothiophen-2-yl)cyclopropanecarbonitrile (0.067 g, 0.292 mM),according to the general procedure C (as described herein above). Yield:0.120 g, 0.267 mM, 91%; ¹H NMR (CDCl₃, 500 MHz) δ 7.38-7.43 (m, 1H),7.35 (d, J=10.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 2H), 7.05-7.15 (m, 1H), 7.03(d, J=4.0 Hz, 1H), 6.90 (d, J=3.0 Hz, 1H) 6.84 (d, J=8.5 Hz, 2H), 5.00(s, 2H), 4.14 (q, J=7.0 Hz, 2H), 2.91 (t, J=8.0 Hz, 2H), 2.60 (t, J=8.0Hz, 2H), 1.75-1.85 (m, 2H), 1.40-1.50 (m, 2H), 1.25 (t, J=7.0 Hz, 3H);MS (m/z) 472.3 [M+Na⁺].

Step 2d

3-(4-((2-(5-(1-Cyanocyclopropyl)thiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)propanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of ethyl3-(4-((2-(5-(1-cyanocyclopropyl)thiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)propanoate(compound obtained in step 2c) (0.100 g, 0.222 mM) with LiOH.H₂O (9.33mg, 0.222 mM), according to the general procedure D (as described hereinabove). Yield: 0.082 g, 0.195 mM, 87%; ¹H NMR (DMSO-d₆, 500 MHz) δ 12.09(s, 1H), 7.45-7.55 (m, 1H), 7.47 (t, J=9.5 Hz, 1H), 7.25-7.35 (m, 1H),7.14 (d, J=8.0 Hz, 2H), 7.05-7.10 (m, 2H), 6.87 (d, J=8.5 Hz, 2H), 5.03(s, 2H), 2.75 (t, J=7.5 Hz, 2H), 2.45-2.50 (m, 2H), 1.75-1.85 (m, 2H),1.45-1.55 (m, 2H); MS (m/z) 444.2 [M+Na⁺].

Example 34-(4-((4-Fluoro-4′-(1-methylcyclopropyl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid

Step 3a

Synthesis of methyl4-(4-((4-fluoro-4′-(1-methylcyclopropyl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanote

The title compound was prepared in an analogous manner as Example 1involving the reaction of 1-bromo-4-(1-methylcyclopropyl)benzene (0.049g, 0.233 mM) was coupled with methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(compound obtained in step 1b of Example 1) (0.150 g, 0.350 mM),potassium carbonate (0.097 g, 0.700 mM), in presence oftetrakis(triphenyl)phosphine)palladium(0) (0.013 g, 0.012 mM), accordingto general procedure C (as described herein above). Yield: 0.050 g,0.116 mM, 49.5%; ¹H NMR (CDCl₃, 300 MHz) δ 7.30-7.38 (m, 1H), 7.20-7.30(m, 5H), 7.00-7.10 (m, 3H), 6.78 (d, J=8.0 Hz, 2H), 4.91 (s, 2H), 3.66(s, 3H), 2.58 (t, J=7.2 Hz, 2H), 2.31 (t, J=7.2 Hz, 2H), 1.85-1.95 (m,2H), 1.45 (s, 3H), 0.91 (bt, J=6.3 Hz, 2H), 0.79 (bt, J=3.5 Hz, 2H); MS(m/z) 433.3 [M+H⁺].

Step 3b

Synthesis of4-(4-((4-fluoro-4′-(1-methylcyclopropyl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((4-fluoro-4′-(1-methylcyclopropyl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoate(compound obtained in step 3a) (0.038 g, 0.088 mM), with LiOH.H₂O (0.018g, 0.439 mM) according to general procedure D (as described hereinabove). Yield: 0.024 g, 0.057 mM, 65.3%; ¹H NMR (DMSO-d₆, 300 MHz) δ:12.03 (s, 1H), 7.36-7.45 (m, 2H), 7.20-7.35 (m, 5H), 7.05 (d, J=8.4 Hz,2H), 6.79 (d, J=8.7 Hz, 2H), 4.91 (s, 2H), 2.45-2.50 (m, 2H), 2.16 (t,J=7.2 Hz, 2H), 1.65-1.80 (m, 2H), 1.38 (s, 3H), 0.85-0.90 (m, 2H),0.70-0.80 (m, 2H); MS m/z 419.2 [M+H⁺].

Example 44-(4-((4′-(1-Cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid

Step 4a

Synthesis of methyl4-(4-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoate

The title compound was prepared in an analogous manner as Example 1involving the reaction of 1-(4-bromophenyl)cyclopropanecarbonitrile(0.045 g, 0.202 mM) with methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(compound obtained in step 1b of Example 1) (0.130 g, 0.304 mM) andpotassium carbonate (0.084 g, 0.607 mM) in the presence oftetrakis(triphenylphosphine)palladium(0) (0.012 g, 10.12 μmol),according to general procedure C (as described herein above). Yield:0.078 g, 0.176 mM, 87%; ¹H NMR (CDCl₃, 300 MHz) δ 7.30-7.40 (m, 5H),7.10-7.30 (m, 2H), 7.06 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.1 Hz, 2H), 4.86(s, 2H), 3.66 (s, 3H), 2.58 (t, J=7.5 Hz, 2H), 2.31 (t, J=7.5 Hz, 2H),1.80-2.00 (m, 2H), 1.60-1.85 (m, 2H), 1.40-1.50 (m, 2H); MS (m/z) 466.3[M+Na⁺].

Step 4b

Synthesis of4-(4-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoate(0.068 g, 0.153 mM) with LiOH.H₂O (0.032 g, 0.767 mM) in water (2mL/mM), according to general procedure D (as described herein above).Yield: 0.055 g, 0.128 mM, 84%; ¹H NMR (DMSO-d₆, 300 MHz) δ 12.03 (s,1H), 7.20-7.50 (m, 7H), 7.05 (d, J=8.1 Hz, 2H), 6.78 (d, J=8.1 Hz, 2H),4.90 (s, 2H), 2.40-2.50 (m, 2H), 2.16 (t, J=7.2 Hz, 2H), 1.65-1.80 (m,4H), 1.45-1.55 (m, 2H); MS (m/z) 452.4 [M+Na⁺].

Example 53-(4-((4′-(1-Cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoicacid

Step 5a

Synthesis of ethyl3-(4-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoate

The title compound was prepared in an analogous manner as Example 1involving the reaction of 1-(4-bromophenyl)cyclopropane carbonitrile(0.052 g, 0.233 mM) with ethyl3-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)propanoate(0.150 g, 0.350 mM) in presence of K₂CO₃ (0.097 g, 0.700 mM) andPd(PPh₃)₄ (0.013 g, 0.012 mM), according to general procedure C (asdescribed herein above). Yield: 0.088 g, 0.198 mM, 85%; ¹H NMR (CDCl₃,300 MHz) δ 7.30-7.40 (m, 5H), 7.22-7.30 (m, 1H), 7.05-7.15 (m, 3H), 6.79(d, J=8.7 Hz, 2H), 4.87 (s, 2H), 4.13 (q, J=6.9 Hz, 2H), 2.89 (t, J=7.5Hz, 2H), 2.58 (t, J=8.1 Hz, 2H), 1.75-1.85 (m, 2H), 1.40-1.50 (m, 2H)1.24 (t, J=7.2 Hz, 3H); MS m/z 466.3 [M+Na⁺].

Step 5b

Synthesis of3-(4-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoicacid

The title compound was prepared in an analogous manner as Example 2involving the reaction of ethyl3-(4-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoate(0.078 g, 0.176 mM) with LiOH.H₂O (0.879 mM) in water (2 mL/mM),according to general procedure D (as described herein above). Yield:0.060 g, 0.144 mM, 82%; ¹H NMR (DMSO-d₆, 300 MHz) δ 12.08 (s, 1H),7.20-7.50 (m, 7H), 7.10 (d, J=8.1 Hz, 2H), 6.78 (d, J=8.1 Hz, 2H), 4.90(s, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.40-2.50 (m, 2H), 1.70-1.85 (m, 2H),1.50-1.60 (m, 2H); MS m/z 438.2 [M+Na⁺].

Example 63-(4-((2-(6-(1-Cyanocyclopropyl)pyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)propanoicacid

Step 6a

Synthesis of ethyl3-(4-((2-(6-(1-cyanocyclopropyl)pyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)propanoate

The title compound was prepared in an analogous manner as Example 2involving the reaction of ethyl3-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)propanoate(0.150 g, 0.350 mM) with 1-(5-bromopyridin-2-yl)cyclopropanecarbonitrile(0.052 g, 0.233 mM), in the presence of K₂CO₃ (0.097 g, 0.700 mM) andtetrakis(triphenyl)phosphine)palladium(0) (0.013 g, 0.012 mM), accordingto general procedure C (as described herein above). Yield: 0.066 g,0.145 mM, 62.2%. ¹H NMR (CDCl₃, 300 MHz) δ 8.34 (s, 1H), 7.65-7.75 (m,2H), 7.37 (dd, J=9.6 Hz, 1H), 7.20-7.30 (m, 1H), 7.05-7.18 (m, 3H), 6.76(d, J=8.7 Hz, 2H), 4.83 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 2.88 (t, J=7.5Hz, 2H), 2.58 (t, J=8.1 Hz, 2H), 1.82-1.90 (m, 2H), 1.70-1.80 (m, 2H),1.23 (t, J=7.2 Hz, 3H); MS m/z 445.3 [M+H⁺].

Step 6b

Synthesis of3-(4-((2-(6-(1-cyanocyclopropyl)pyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)propanoicacid

The title compound was prepared in an analogous manner as Example 2involving the reaction of ethyl3-(4-((2-(6-(1-cyanocyclopropyl)pyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)propanoate(0.060 g, 0.135 mM) with LiOH.H₂O (5.67 mg, 0.135 mM) in water (2mL/mM), according to general procedure D (as described herein above).Yield: 0.045 g, 0.108 mM, 80%; ¹H NMR (DMSO-d₆, 300 MHz) δ 12.06 (s,1H), 8.51 (s, 1H), 7.87 (dd, J=8.1 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H),7.25-7.50 (m, 3H), 7.09 (d, J=8.7 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 4.91(s, 2H), 2.71 (t, J=7.5 Hz, 2H), 2.35-2.60 (m, 2H), 1.75-1.90 (m, 2H),1.65-1.70 (m, 2H); MS (m/z) 417.2 [M+H^(+]).

Example 74-(4-((4′-Cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid

Step 7a

Synthesis of methyl4-(4-((4′-cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoate

The title compound was prepared in an analogous manner as Example 1involving the reaction of 1-bromo-4-cyclopropylbenzene (0.032 g, 0.163mM) withmethyl-4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(0.07 g, 0.163 mM) and potassium carbonate (0.068 g, 0.49 mM) in thepresence of tetrakis(triphenyl)phosphine palladium(0) (0.003 g, 0.008mM), according to general procedure C (as described herein above).Yield: 0.035 g, 0.084 mM, 51%; ¹H NMR (CDCl₃, 300 MHz) δ 7.32-7.35 (m,2H), 7.21-7.24 (m, 2H), 7.04-7.12 (m, 5H), 6.77 (d, J=8.4 Hz, 2H) 4.90(s, 2H), 3.66 (s, 3H), 2.50 (t, J=7.2 Hz, 2H), 2.31 (t, J=7.2 Hz 2H),1.88-1.93 (m, 3H), 0.99-1.02 (m, 2H), 0.73-0.75 (m, 2H) LC-MS (m/z)419.3 [M+H⁺].

Step 7b

Synthesis of4-(4-((4′-cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((4′-cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoate(0.03 g, 0.071 mM) with LiOH.H₂O (0.015 g, 0.356 mM), general procedureD (as described herein above). Yield: 0.022 g, 0.054 mM, 76%; ¹H NMR(DMSO d₆, 300 MHz) δ 12.03 (s, 1H), 7.31-7.40 (m, 2H), 7.26 (d, J=8.4Hz, 3H), 7.04-7.12 (m, 4H), 6.79 (d, J=8.4 Hz, 2H) 4.89 (s, 2H), 2.52(m, 2H), 2.17 (t, J=7.5 Hz, 2H), 1.93 (m, 1H), 1.70-1.75 (m, 2H),0.93-0.94 (m, 2H), 0.67-0.69 (m, 2H); MS (m/z) 427.2 [M+Na⁺].

Example 84-(4-((2-(2,3-Dihydro-1H-inden-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 8a

Synthesis of methyl4-(4-((2-(2,3-dihydro-1H-inden-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as Example 1involving the reaction of 5-bromo-2,3-dihydro-1H-indene (0.053 g, 0.269mM) withmethyl-4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(0.150 g, 0.350 mM) and potassium carbonate (0.112 g, 0.808 mM) in thepresence of tetrakis(triphenylphosphine)palladium(0) (0.016 g, 0.013mM), according to general procedure C (as described herein above).Yield: 0.098 g, 0.234 mM, 87%; ¹H NMR (CDCl₃, 300 MHz) δ 7.32-7.38 (m,1H), 7.28-7.31 (m, 1H), 7.18-7.28 (m, 2H), 7.00-7.12 (m, 4H), 6.78 (d,J=8.7 Hz, 2H), 4.92 (s, 2H), 3.66 (s, 3H), 2.93 (q, J=7.5 Hz, 4H), 2.57(t, J=7.5 Hz, 2H), 2.31 (t, J=7.5 Hz, 2H), 2.05-2.20 (m, 2H), 1.80-2.00(m, 2H); MS (m/z) 441.1 [M+Na⁺].

Step 8b

Synthesis of4-(4-((2-(2,3-dihydro-1H-inden-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(2,3-dihydro-1H-inden-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoate(0.080 g, 0.191 mM) with LiOH.H₂O (0.040 g, 0.956 mM), general procedureD (as described herein above). Yield: 0.050 g, 0.124 mM, 64.7%; ¹H NMR(DMSO-d₆, 300 MHz) δ 12.03 (s, 1H), 7.30-7.50 (m, 2H), 7.18-7.28 (m,3H), 7.12 (d, J=7.8 Hz, 1H), 7.05 (d, J=8.4 Hz, 2H), 6.79 (d, J=8.7 Hz,2H), 4.89 (s, 2H), 2.75-2.85 (m, 4H), 2.40-2.50 (m, 2H), 2.16 (t, J=7.5Hz, 2H), 1.95-2.05 (m, 2H), 1.65-1.85 (m, 2H); MS (m/z) 427.4 [M+Na⁺].

Example 94-(4-((5-Fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid

Step 9a

Synthesis of methyl4-(4-((5-fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)butanoate (0.50 g, 1.312 mM)with (5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid (0.346 g, 1.967 mM)in presence of Tetrakis(triphenylphosphine)palladium(0) (0.076 g, 0.066mM), according to general procedure C (as described herein above) Yield:0.528 g, 1.221 mM, 93%; ¹H NMR (CDCl₃, 300 MHz) δ 7.30-7.38 (m, 1H),7.20-7.30 (m, 1H), 6.95-7.15 (m, 6H), 6.79 (d, J=8.7 Hz, 2H), 4.92 (s,2H), 3.66 (s, 3H), 2.69-2.85 (m, 4H), 2.58 (t, J=7.5 Hz, 2H), 2.31 (t,J=7.5 Hz, 2H), 1.85-2.00 (m, 2H), 1.75-1.85 (m, 4H); MS m/z 455.1[M+Na⁺].

Step 9b

Synthesis of4-(4-((5-fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((5-fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoate(0.50 g, 1.156 mM) with LiOH.H₂O (0.243 g, 5.78 mM), according togeneral procedure D (as described herein above). Yield: 0.428 g, 1.023mM, 88%; ¹H NMR (DMSO-d₆, 300 MHz) δ 12.03 (s, 1H), 7.15-7.45 (m, 3H),7.00-7.15 (m, 5H), 6.80 (d, J=8.4 Hz, 2H), 4.88 (s, 2H), 2.60-2.75 (m,4H), 2.40-2.50 (m, 2H), 2.16 (t, J=7.2 Hz, 2H), 1.60-1.80 (m, 6H); MS(m/z) 441.1 [M+Na⁺].

Example 104-(4-((2-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 10a

Synthesis of methyl4-(4-((2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as Example 1involving the reaction of bicyclo[4.2.0]octa-1(6),2,4-trien-3-ylboronicacid (0.04 g, 0.275 mM) with methyl4-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)butanoate (0.04 g, 0.184 mM)and potassium carbonate (0.076 g, 0.551 mM) in the presence oftetrakis(triphenylphosphine)palladium(0) (0.003 g, 0.009 mM), accordingto general procedure C (as described herein above). Yield: 0.068 g,0.168 mM, 92%; ¹H NMR (CDCl₃, 300 MHz) δ 7.36 (d, J=9.9 Hz, 1H),7.01-7.251 (m, 7H), 6.78 (d, J=8.7 Hz, 2H), 4.90 (s, 2H), 3.66 (s, 3H),3.22 (s, 4H), 2.56 (t, J=7.5 Hz, 2H), 2.28-2.31 (m, 2H), 1.93-1.96 (m,2H); MS (m/z) 427.2 [M+Na⁺].

Step 10b

Synthesis of4-(4-((2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoate(0.06 g, 0.148 mM) with LiOH.H₂O (0.031 g, 0.956 mM), according togeneral procedure D (as described herein above). Yield: 0.040 g, 0.102mM, 69.1%; ¹H NMR (CDCl₃, 300 MHz) δ 7.35 (dd J=2.7, 9.9 Hz, 1H),7.22-7.26 (m, 2H), 7.01-7.14 (m, 5H), 6.78 (d, J=8.4 Hz, 2H), 4.90 (s,2H), 3.21 (s, 4H), 2.60 (t, J=7.5 Hz, 2H), 2.32-2.37 (m, 2H), 1.87-1.97(m, 2H); MS (m/z) 413.2 [M+Na⁺].

Example 114-(4-((2-(5-Cyclopropylthiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 11a

Synthesis of methyl4-(4-((2-(5-cyclopropylthiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(100 mg, 0.233 mM) with 2-bromo-5-cyclopropylthiophene (61.6 mg, 0.304mM) and potassium carbonate (81 mg, 0.584 mM) in the presence of(tetrakistriphenylphosphine)palladium(0) (16.19 mg, 0.014 mM), accordingto general procedure C (as described herein above). Yield: 82.3 mg, 83%;¹H NMR (500 MHz, CDCl₃) δ: 7.42-7.39 (m, 1H), 7.35-7.34 (m, 1H), 7.09(d, J=8.5 Hz, 2H), 7.06-7.03 (m, 1H), 6.86-6.84 (m, 3H), 6.73-6.72 (m,1H), 5.05 (s, 2H), 3.68 (s, 3H), 2.60 (t, J=7.5 Hz, 2H), 2.33 (t, J=7.5Hz, 2H), 2.15-2.02 (m, 1H), 1.97-1.91 (m, 2H), 1.02 (dd, J=7.00 Hz, 2H),0.68 (dd, J=6.00 Hz, 2H); MS (E/Z): 425.1 (M+H), 447.1 (M+Na).

Step 11b

Synthesis of4-(4-((2-(5-cyclopropylthiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(5-cyclopropylthiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate(75 mg, 0.177 mM) with LiOH.H₂O (589 μl, 0.883 mM), according to generalprocedure D (as described herein above). Yield: 64.2 mg, 0.156 mM, 89%;¹H NMR (500 MHz, DMSO-d₆) δ: 12.04 (bs, 1H), 7.49-7.43 (m, 2H),7.27-7.24 (m, 1H), 7.10 (d, J=8.0 Hz, 2H), 6.97 (d, J=3.5 Hz, 1H), 6.88(d, J=8.5 Hz, 2H), 6.80 (d, J=3.0 Hz, 1H), 5.02 (s, 2H), 2.53-2.50 (m,2H), 2.19 (t, J=7.0 Hz, 2H), 2.12-2.10 (m, 1H), 1.77-1.74 (m, 1H), 0.98(dd, J=6.5 Hz, 2H), 0.66 (dd, J=7.0 Hz, 2H); MS (E/Z): 433.2 (M+Na).

Example 124-(4-((5-Fluoro-2-(5-(1-hydroxycyclobutyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoicacid

Step 12a

Synthesis of 1-(5-bromothiophen-2-yl)cyclobutanol

To a stirred solution of 2,5-dibromothiophene (949 mg, 3.92 mM)dissolved in dry THF at −78° C., n-butyllithium was added (2943 μl, 4.71mM). The mixture was allowed to stir for 30 min and then cyclobutanone(550 mg, 7.85 mM) was slowly added for 2 min. After completion ofreaction, the reaction mixture was quenched with ammonium chloride,extracted with ethyl acetate, dried over sodium sulphate and purified bycolumn chromatography to give 1-(5-bromothiophen-2-yl)cyclobutanol. ¹HNMR (300 MHz, CDCl₃) δ: 6.91 (d, J=3.9 Hz, 1H), 6.81 (d, J=3.9 Hz, 1H),2.54-2.36 (m, 4H), 2.28 (bs, 1H), 2.01-1.88 (m, 1H), 1.80-1.65 (m, 1H),HPLC: 99.46%; MS (E/Z): 256.3 (M+Na).

Step 12b

Synthesis of methyl4-(4-((5-fluoro-2-(5-(1-hydroxycyclobutyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as Example 1involving the reaction of 1-(5-bromothiophen-2-yl)cyclobutanol (56.6 mg,0.243 mM) withmethyl-4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(compound obtained in step 1b of Example 1) (80 mg, 0.187 mM), potassiumcarbonate (64.5 mg, 0.467 mM), in the presence oftetrakis(triphenyl)phosphine)palladium(0) (12.95 mg, 0.011 mM) accordingto general procedure C (as described herein above). Yield: 63.7 mg,0.119 mM, 63.8%; ¹H NMR (500 MHz, CDCl₃) δ: 7.46-7.41 (m, 1H), 7.37-7.11(m, 1H), 7.91 (d, J=8.7 Hz, 2H), 7.15 (d, J=3.6 Hz, 2H), 7.92 (d, J=3.6Hz, 2H), 7.84 (d, J=8.7 Hz, 2H), 5.05 (s, 2H), 3.67 (s, 3H), 2.68-2.53(m, 4H), 2.52-2.47 (m, 2H), 2.35-2.30 (m, 2H), 1.97-1.87 (m, 3H),1.82-1.73 (m, 1H); MS (E/Z): 477.1 (M+Na).

Step 12c

Synthesis of4-(4-((5-fluoro-2-(5-(1-hydroxycyclobutyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((5-fluoro-2-(5-(1-hydroxycyclobutyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoate(82 mg, 0.180 mM) with LiOH.H₂O (37.8 mg, 0.902 mM) according to generalprocedure D (as described herein above). Yield: 67.8 mg, 0.153 mM, 85%;¹H NMR (300 MHz, DMSO-d₆) δ: 12.04 (bs, 1H), 7.58-7.43 (m, 2H),7.30-7.24 (m, 1H), 7.10 (d, J=8.4 Hz, 2H), 7.03 (s, 2H), 7.87 (d, J=8.4Hz, 2H), 7.92 (d, J=3.6 Hz, 2H), 7.84 (d, J=8.7 Hz, 2H), 5.96 (bs, 2H),5.04 (s, 2H), 2.55-2.47 (m, 4H), 2.34-2.25 (m, 2H), 2.18 (t, J=7.5 Hz,2H), 1.79-1.61 (m, 4H); MS (E/Z): 463.2 (M+Na).

Example 133-(4-((4-Fluoro-4′-(oxetan-3-yl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoicacid

Step 13a

Synthesis of 3-(4-bromophenyl)oxetane

To a solution of (4-bromophenyl)boronic acid (250 mg, 1.245 mM),trans-2-aminocyclohexanol hydrochloride (6.91 mg, 0.06 mM) and sodiumhexamethyldisilazane (1.867 ml, 1.867 mM) was added nickel(II) iodide(18.75 mg, 0.06 mM) and the mixture was degassed with argon for 2-5 min.To the resulting solution isopropyl alcohol (2 ml) was added and themixture was stirred under argon for 5-10 min and then 3-iodooxetane (183mg, 0.996 mM) was added. The mixture was then allowed heat at 80° C.under microwave irradiation for 20-30 min. After completion of reaction,the mixture was quenched by adding saturated ammonium chloride,extracted with ethyl acetate, dried over sodium sulphate, concentratedand purified by column chromatography to get 3-(4-bromophenyl)oxetane.Yield: 80 mg, 0.320 mM, 25.7%; ¹H NMR (300 MHz, DMSO-d₆): δ 7.52 (d,J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 5.15 (d, J=5.1 Hz, 2H), 5.15-5.07(m, 2H), 4.84-4.81 (m, 1H)

Step 13b

Synthesis of ethyl3-(4-((4-fluoro-4′-(oxetan-3-yl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoate

The title compound was prepared in an analogous manner as step-2c ofExample 2 involving the reaction of ethyl3-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)propanoate(120 mg, 0.279 mM) with 3-(4-bromophenyl)oxetane (71.3 mg, 0.334 mM),according to general procedure C (as described herein above). Yield: 77mg, 0.175 mM, 62.7%; ¹H NMR (300 MHz, CDCl₃) δ: 7.46-7.34 (m, 6H),7.30-7.24 (m, 1H), 7.93 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H),4.96-4.92 (m, 4H), 4.63 (d, J=6.3 Hz, 2H), 4.31-4.26 (m, 1H), 4.01 (q,J=7.2 Hz, 2H), 2.75 (t, J=7.5 Hz, 2H), 2.53 (t, J=7.5 Hz, 2H), 1.08 (t,J=6.3 Hz, 3H); MS (E/Z): 457.2 (M+Na).

Step 13c

Synthesis of3-(4-((4-fluoro-4′-(oxetan-3-yl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoicacid

The title compound was prepared in an analogous manner as Example 2involving the reaction of ethyl3-(4-((4-fluoro-4′-(oxetan-3-yl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoate(45 mg, 0.104 mM) with LiOH.H₂O (21.84 mg, 0.518 mM), according togeneral procedure D (as described herein above). Yield: 39.8 mg, 0.090mM, 87.3%; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.07 (bs, 1H), 7.43-7.34 (m,6H), 7.30-7.24 (m, 1H), 7.97 (d, J=8.7 Hz, 2H), 6.78 (d, J=8.7 Hz, 2H),4.96-4.92 (m, 4H), 4.64 (d, J=6.3 Hz, 2H), 4.33-4.26 (m, 1H), 2.72 (t,J=7.8 Hz, 2H), 2.46 (t, J=7.5 Hz, 2H); MS (E/Z): 407.1 (M+H), 405.0(M−H).

Example 143-(4-((4-Fluoro-4′-(1-hydroxycyclobutyl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoicacid

Step 14a

Synthesis of 1-(4-bromophenyl)cyclobutanol

The title compound was prepared in an analogous manner as step-15a ofExample 15 involving the reaction of 1,4-dibromobenzene (1.683 g, 7.13mM) with cyclobutanone (1 g, 14.27 mM). Yield: 2.74 g, 12.06 mM, 84.5%;¹H NMR (300 MHz, CDCl₃) δ: 7.51 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz,1H), 5.55 (bs, 1H), 2.38-2.20 (m, 4H), 1.98-1.85 (m, 1H), 1.70-1.58 (m,1H); MS (E/Z): 226.2 (M−1).

Step 14b

Synthesis of ethyl3-(4-((4-fluoro-4′-(1-hydroxycyclobutyl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoate

The title compound was prepared in an analogous manner as step-2c ofExample 2 involving the reaction of ethyl3-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)propanoate(165 mg, 0.385 mM) with 1-(4-bromophenyl)cyclobutanol (105 mg, 0.462mM), according to general procedure C (as described herein above).Yield: 120 mg, 0.265 mM, 68.7%; ¹H NMR (300 MHz, CDCl₃) δ: 7.56 (d,J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.30-7.27 (m, 1H), 7.11-7.05 (m,4H), 6.79 (d, J=8.4 Hz, 2H), 4.92 (s, 2H), 4.13 (q, J=7.2 Hz, 2H), 2.89(t, J=7.8 Hz, 2H), 2.67-2.55 (m, 4H), 2.46-2.37 (m, 2H), 2.12-2.00 (m,3H), 1.26 (t, J=6.3 Hz, 3H); MS (E/Z): 471.3 (M+Na).

Step 14c

Synthesis of3-(4-((4-fluoro-4′-(1-hydroxycyclobutyl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoicacid

The title compound was prepared in an analogous manner as Example 2involving the reaction of ethyl3-(4-((4-fluoro-4′-(1-hydroxycyclobutyl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoate(60 mg, 0.134 mM) with LiOH.H₂O (28.14 mg, 0.669 mM) according togeneral procedure D (as described herein above). Yield: 50.9 mg, 0.112mM, 83.8%; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.07 (bs, 1H), 7.53 (d, J=8.1Hz, 2H), 7.41-7.35 (m, 4H), 7.29-7.27 (m, 1H), 7.10 (d, J=8.1 Hz, 2H),6.78 (d, J=8.4 Hz, 2H), 5.52 (bs, 1H), 4.92 (s, 2H), 2.72 (t, J=7.5 Hz,2H), 2.49-2.36 (m, 4H), 2.31-2.22 (m, 2H), 2.12-2.00 (m, 2H); MS (E/Z):421.3 (M+H).

Example 153-(4-((4′-(5,5-Dimethylcyclopent-1-en-1-yl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoicacid

Step 15a

Synthesis of 1-(4-bromophenyl)-2,2-dimethylcyclopentanol

The title compound was prepared in an analogous manner as step-15a ofExample 15 involving the reaction of 1,4-dibromobenzene (1577 mg, 6.69mM) with 2,2-dimethylcyclopentanone (500 mg, 4.46 mM). Yield: 1077 mg,4.00 mM, 89.8%; ¹H NMR (300 MHz, CDCl₃) δ: 7.49-7.39 (m, 4H), 4.37 (bs,1H), 2.60-2.54 (m, 1H), 1.89-1.70 (m, 4H), 1.49-1.43 (m, 1H), 0.84 (s,3H), 0.53 (s, 3H); MS (E/Z): 270.1 (M+1).

Step 15b

Synthesis of ethyl3-(4-((4-fluoro-4′-(1-hydroxy-2,2-dimethylcyclopentyl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoate

The title compound was prepared in an analogous manner as step-2c ofExample 2 involving the reaction of ethyl3-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)propanoate(159 mg, 0.372 mM) with 1-(4-bromophenyl)-2,2-dimethylcyclopentanol (100mg, 0.372 mM), according to general procedure C (as described hereinabove). Yield: 125 mg, 0.237 mM, 63.8%; ¹H NMR (300 MHz, CDCl₃) δ: 7.31(d, J=4.2 Hz, 2H), 7.30-7.27 (m, 3H), 7.10-7.04 (m, 4H), 6.77 (d, J=8.4Hz, 2H), 4.92 (s, 2H), 4.13 (q, J=6.9 Hz, 2H), 2.91-2.84 (m, 2H),2.60-2.53 (m, 2H), 2.00-2.81 (m, 4H), 1.68-1.59 (m, 2H), 1.24 (t, J=7.2Hz, 3H), 1.03 (s, 3H), 0.68 (s, 3H); MS (E/Z): 513.2 (M+Na).

Step 15c

Synthesis of ethyl3-(4-((4′-(5,5-dimethylcyclopent-1-en-1-yl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoate

To a stirred solution ofethyl-3-(4-((4-fluoro-4′-(1-hydroxy-2,2-dimethylcyclopentyl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoate(95 mg, 0.194 mM) dissolved in Toluene (5 ml), 4-methylbenzenesulfonicacid (33.3 mg, 0.194 mM) was added and the mixture was allowed to refluxat 110° C. for 30 min. After completion of reaction, the mixture wasquenched with water and extracted with ethyl acetate and purified bycolumn chromatography. Yield: 70.0 mg, 0.139 mM, 72%; ¹H NMR (300 MHz,CDCl₃) δ: 7.40 (d, J=8.4 Hz, 2H), 7.330-7.26 (m, 3H), 7.10-7.06 (m, 4H),6.80-6.76 (m, 2H), 5.84 (t, J=7.5 Hz, 1H), 4.94 (s, 2H), 4.13 (q, J=6.9Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.58 (t, J=7.5 Hz, 2H), 2.43-2.38 (m,3H), 1.89 (t, J=6.9 Hz, 2H), 1.58 (s, 3H), 1.52 (t, J=6.9 Hz, 2H), 1.24(s, 3H); MS (E/Z): 495.2 (M+Na).

Step 15d

Synthesis of3-(4-((4′-(5,5-dimethylcyclopent-1-en-1-yl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoicacid

The title compound was prepared in an analogous manner as Example 2involving the reaction of ethyl3-(4-((4′-(5,5-dimethylcyclopent-1-en-1-yl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoate(60 mg, 0.127 mM) with LiOH.H₂O (26.6 mg, 0.635 mM), according togeneral procedure D (as described herein above). Yield: 50.1 mg, 0.113mM, 88.7%; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.07 (bs, 1H), 7.40 (d, J=8.4Hz, 2H), 7.30-7.25 (m, 3H), 7.11-7.06 (m, 4H), 6.81-6.77 (m, 2H), 5.84(t, J=7.5 Hz, 1H), 2.90 (t, J=7.5 Hz, 2H), 2.64 (t, J=7.5 Hz, 2H), 2.58(t, J=7.5 Hz, 2H), 2.43-2.37 (m, 2H), 1.89 (t, J=6.9 Hz, 2H), 1.27 (s,6H); MS (E/Z): 445.2 (M+1), 443.2 (M−1).

Example 164-(4-((4′-Cyclohexyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid

Step 16a

Synthesis of methyl4-(4-((4′-cyclohexyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step-1c ofExample 1 involving the reaction of (4-cyclohexylphenyl)boronic acid (92mg, 0.449 mM) with methyl4-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)butanoate (114 mg, 0.299 mM),and potassium carbonate (104 mg, 0.748 mM) in presence oftetrakis(triphenyl)phosphine palladium(0) (20.73 mg, 0.018 mM),according to general procedure C (as described herein above). Yield:91.3 mg, 0.198 mM, 66.3%; ¹H NMR (300 MHz, CDCl₃) δ: 7.36-7.31 (m, 2H),7.29-7.25 (m, 4H), 7.11-7.04 (m, 3H), 7.78 (t, J=8.4 Hz, 2H), 4.92 (s,2H), 3.66 (s, 3H), 2.58 (t, J=7.8 Hz, 4H), 2.31 (t, J=7.5 Hz, 2H),1.96-1.88 (m, 6H), 1.48-1.34 (m, 3H); MS (E/Z): 483.3 (M+Na).

Step 16b

Synthesis of4-(4-((4′-cyclohexyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((4′-cyclohexyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoate(80 mg, 0.174 mM) with LiOH.H₂O (36.5 mg, 0.868 mM), according togeneral procedure D (as described herein above). Yield: (70 mg, 0.151mM, 87%; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.04 (bs, 1H), 7.41-7.32 (m, 2H),7.29-7.22 (m, 5H), 7.55 (t, J=8.4 Hz, 2H), 6.78 (t, J=8.4 Hz, 2H), 4.90(s, 2H), 2.49-2.46 (m, 4H), 2.16 (t, J=7.2 Hz, 2H), 1.79-1.67 (m, 6H),1.42-1.33 (m, 3H), 1.30-1.23 (m, 2H); MS (E/Z): 444.8 (M+1), 469.2(M+Na).

Example 173-(4-((5-Fluoro-2-(6-(oxetan-3-yl)pyridin-3-yl)benzyl)oxy)phenyl)propanoicacid

Step 17a

Synthesis of ethyl3-(4-((5-fluoro-2-(pyridin-3-yl)benzyl)oxy)phenyl)propanoate

The title compound was prepared in an analogous manner as step 2b ofExample 2 involving the reaction ofethyl-3-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)propanoate (100 mg, 0.262mM) with pyridin-3-ylboronic acid (64.5 mg, 0.525 mM), according togeneral procedure C (as described herein above). Yield: (64.1 mg, 0.167mM, 63.8%); ¹H NMR (300 MHz, DMSO-d₆) δ: 12.01 (bs, 1H), 8.62 (s, 1H),7.80 (d, J=6.3 Hz, 2H), 7.45-7.32 (m, 3H), 6.92 (d, J=8.1 Hz, 2H), 6.78(d, J=8.1 Hz, 2H), 4.92 (s, 1H), 4.89-4.69 (m, 4H), 4.42-4.38 (m, 1H),2.72 (t, J=7.5 Hz, 2H), 2.46 (t, J=7.5 Hz, 2H); MS (E/Z): 408.2 (M+1).

Step 17b

Synthesis of ethyl3-(4-((5-fluoro-2-(6-(oxetan-3-yl)pyridin-3-yl)benzyl)oxy)phenyl)propanoate

The title compound was prepared according to the literature procedure(J. Org. Chem., 74 (16), 2009, pp. 6354-6357) involving the reaction ofethyl-3-(4-((5-fluoro-2-(pyridin-3-yl)benzyl)oxy)phenyl)propanoate (200mg, 0.527 mM), concentrated sulphuric acid (103 mg, 1.054 mM),3-iodooxetane (145 mg, 0.791 mM) and iron (II) sulphate heptahydrate(68.9 mg, 0.158 mM) in DMSO (10 mL), hydrogen peroxide (23.31 mg, 0.685mM) (30% in water) was added drop wise over 1-2 min at room temperature.After 1-2 min, further portion of iron (II) sulphate heptahydrate (0.3mol) was added and the mixture was stirred for 30 min. Further iron (II)sulphate heptahydrate (0.3 mol) was added, and the mixture was stirredfor 15 min. After completion of reaction, the mixture was poured into0.2 m solution of sodium hydroxide and extracted with ethyl acetate,concentrated. The crude product was used as it is for further reactionwithout any purification.

Step 17c

Synthesis of3-(4-((5-fluoro-2-(6-(oxetan-3-yl)pyridin-3-yl)benzyl)oxy)phenyl)propanoicacid

The title compound was prepared in an analogous manner as Example 2involving the reaction of ethyl3-(4-((5-fluoro-2-(6-(oxetan-3-yl)pyridin-3-yl)benzyl)oxy)phenyl)propanoate(40 mg, 0.092 mM) with LiOH.H₂O (19.3 mg, 0.459 mM), according togeneral procedure D (as described herein above). Yield: 32.6 mg, 0.071mM, 77.8%; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.01 (bs, 1H), 8.62 (s, 1H),7.80 (d, J=6.3 Hz, 2H), 7.45-7.32 (m, 3H), 6.92 (d, J=8.1 Hz, 2H), 6.78(d, J=8.1 Hz, 2H), 4.92 (s, 1H), 4.89-4.69 (m, 4H), 4.42-4.38 (m, 1H),2.72 (t, J=7.5 Hz, 2H), 2.46 (t, J=7.5 Hz, 2H); MS (E/Z): 408.2 (M+1).

Example 183-(5-((4′-(1-Cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)propanoicacid

Step 18a

Synthesis of 5-((2-bromo-5-fluorobenzyl)oxy)picolinaldehyde

To a stirred solution of2-(2-(bromomethyl)-4-fluorophenyl)-5-methylthiophene (0.200 g, 1.625 mM)and 5-hydroxypicolinaldehyde (0.435 g, 1.625) in dry acetonitrile,cesium carbonate (0.794 g, 2.43 mM) was added and stirred overnight. Themixture was filtered and residue was washed with acetonitrile. Thefiltrate was concentrated to give5-((2-bromo-5-fluorobenzyl)oxy)picolinaldehyde. Yield: 0.38 g, 76%; ¹HNMR (300 MHz, DMSO-d₆) δ: 9.90 (s, 1H), 8.62-8.61 (d, J=8.7 Hz, 1H),7.99-7.96 (d, J=9.3 Hz, 1H), 7.77-7.70 (m, 2H), 7.57-7.53 (dd, J=3, 9.3Hz, 1H), 7.28-7.22 (m, 1H), 5.31 (s, 2H); MS (E/Z): 311.9 (M+1).

Step 18b

Synthesis of (E)-ethyl3-(5-((2-bromo-5-fluorobenzyl)oxy)pyridin-2-yl)acrylate

To a stirred solution of 5-((2-bromo-5-fluorobenzyl)oxy)picolinaldehyde(0.500 g, 1.612 mM) and ethyl 2-(diethoxyphosphoryl) acetate (0.434 g,1.93 5 mM) in dry THF at 0° C., sodium hydride (0.077 g, 1.935 mM) wasadded and stirred at RT for overnight. The mixture was diluted withethyl acetate and washed with brine. The organic layer was dried oversodium sulfate and concentrated to give the title compound. Yield: 0.360g, 58.7%; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.46-8.45 (d, J=2.7 Hz, 1H),7.78-7.71 (m, 2H), 7.65-7.60 (d, T=15.6 Hz, 1H), 7.58-7.50 (m, 2H),7.27-7.21 (m, 1H), 6.76-6.71 (d, T=15.6 Hz, 1H), 5.23 (s, 2H), 4.22-4.15(m, 2H), 1.27-1.22 (t, 3H); MS (E/Z): 382.6 (M+1).

Step 18c

Synthesis of (E)-ethyl3-(5-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)acrylate

The mixture of (E)-ethyl3-(5-((2-bromo-5-fluorobenzyl)oxy)pyridin-2-yl)acrylate (0.150 g, 0.345mM), (4-(1-cyano cyclopropyl)phenyl)boronic acid (0.081 g, 0.431 mM),sodium carbonate (0.136 g, 0.986 mM) and bistriphenylphosphine palladiumdichloride (0.023 g, 0.020 mM) was stirred in microwave at 111° C. for15 min. The mixture was cooled, diluted with ethyl acetate and filteredthrough Celite®. The filtrate was concentrated, purified over silica gelusing ethyl acetate or PET as eluent to give the title compound. Yield:0.078 g, 44.7%; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.30 (s, 1H), 7.71-7.69 (d,J=8.1 Hz, 1H), 7.62-7.57 (d, J=15.9 Hz, 1H), 7.51-7.47 (m, 1H),7.43-7.29 (m, 7H), 6.63-6.68 (d, J=15.9 Hz, 1H) 5.07 (s, 2H), 4.21-4.14(m, 2H), 1.78-1.74 (q, 2H), 1.54-1.49 (m, 2H), 1.27-1.22 (t, 3H); MS(E/Z): 443.3 (M+1).

Step 18d

Synthesis of ethyl3-(5-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)propanoate

To a stirred solution of (E)-ethyl3-(5-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)acrylate(0.090 g, 0.203 mM) in methanol (5 ml), nickel chloride hexahydrate(0.015 g g, 0.061 mM) was added at room temperature. The mixture wascooled and sodium borohydride (0.015 g, 0.407 mM) was added to it. Themixture was allowed to stand at room temperature and stirred for 2 h.The mixture was then filtered through Celite® and purified over silicagel using methanol/chloroform as eluent to the tilte compound. Yield:0.080 g, 88%; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.10 (s, 1H), 7.40-7.37 (m,6H), 7.21-7.17 (m, 3H), s4.98 (s, 2H), 4.00 (q, 2H), 2.90 (t, 2H), 2.65(t, 2H), 1.76 (t, 2H), 1.53 (t, 2H), 1.12 (t, 3H); MS (E/Z): 445.5(M+1).

Step 18e

Synthesis of3-(5-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)propanoic acid

The title compound was prepared in an analogous manner as Example 2involving the reaction of ethyl3-(5-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)propanoate(0.080 g, 0.180 mM) with LiOH.H₂O (1.080 mM), according to generalprocedure D (as described herein above). Yield: 0.051 g, 68%; ¹H NMR(300 MHz, DMSO-d₆) δ: 8.11 (s, 1H), 7.38-7.21 (m, 6H), 7.21-7.15 (m,3H), 4.99 (s, 2H), 2.87 (t, 2H), 2.58 (t, 2H), 1.76 (t, 2H), 1.54 (t,2H); MS (E/Z): 417.5 (M+1).

Example 194-(4-((4-(4-(1-Cyanocyclopropyl)phenyl)pyridin-3-yl)methoxy)phenyl)butanoicacid

Step 19a

Synthesis of 1-(4-(3-formylpyridin-4-yl)phenyl)cyclopropanecarbonitrile

The title compound was prepared in an analogous manner as generalprocedure C involving the reaction of 4-bromonicotinaldehyde (0.200 g,1.075 mM) with (4-(1-cyanocyclopropyl)phenyl)boronic acid (0.302 g,1.613 mM) in the presence of tetrakis(triphenylphosphine)palladium(0)(0.062 g, 0.054 mM). Yield: 0.175 g (65.6%); ¹H NMR (300 MHz, DMSO-d₆)δ: 10.06 (s, 1H), 9.18 (s, 1H), 8.85 (d, J=6 Hz, 2H), 7.47-7.26 (m, 4H),1.87-1.85 (m, 2H), 1.53-1.49 (m, 2H). MASS: MS (e/z): 249 (M+1).

Step 19b

Synthesis of1-(4-(3-(hydroxymethyl)pyridin-4-yl)phenyl)cyclopropanecarbonitrile

1-(4-(3-formylpyridin-4-yl)phenyl)cyclopropanecarbonitrile (0.170 g,0.685 mM) was dissolved in MeOH (10 ml), the mixture was cooled to 0° C.Then sodium(I)tetrahydroborate salt (0.031 g, 0.822 mM) was added slowlydropwise under inert atmosphere. The reaction mass was allowed to standto room temperature and stirred for 1 h. The solvent was removed undervacuum, quenched with water and extracted using ethyl acetate (25 ml×4).The organic layers were combined, dried over anhydrous sodium sulphate,concentrated and purified by column chromatography (50% ethylacetate:PET ether) to give the title compound. Yield: 0.146 g, 85%; ¹HNMR (300 MHz, DMSO-d₆) δ: 8.76 (s, 1H), 8.60 (d, J=5.1 Hz, 1H),7.46-7.38 (m, 4H), 7.22 (d, J=4.8 Hz, 1H), 4.66 (s, 2H), 1.83-1.79 (m,2H), 1.50-1.46 (m, 2H); MS (E/Z): 251 (M+1).

Step 19c

Synthesis of1-(4-(3-(chloromethyl)pyridin-4-yl)phenyl)cyclopropanecarbonitrile

1-(4-(3-(hydroxymethyl)pyridin-4-yl)phenyl)cyclopropanecarbonitrile(0.140 g, 0.559 mM) was dissolved in DCM (2 ml) and the reaction masswas cooled at 0° C. Thionyl chloride (0.041 ml, 0.559 mM) was addedslowly to the mixture. The ice bath was removed, the mixture was broughtto room temperature and stirred reaction mass for 1 h. The reaction masswas quenched with water and extracted with DCM (10 ml×4). The organiclayers were combined and washed with sodium bicarbonate solution (10ml×2). The organic layers were dried over anhydrous sodium sulphate,concentrated to give the title compound. Yield: 0.140 g, 93%.

Step 19d

Synthesis of methyl4-(4-((4-(4-(1-cyanocyclopropyl)phenyl)pyridin-3-yl)methoxy)phenyl)butanoate

1-(4-(3-(chloromethyl)pyridin-4-yl)phenyl)cyclopropanecarbonitrile(0.140 g, 0.521 mM) was dissolved in acetonitrile (5 ml). cesiumcarbonate (0.509 g, 1.563 mM), followed by methyl4-(4-hydroxyphenyl)butanoate (0.111 g, 0.573 mM) was added, and reactionmass was stirred at room temperature for overnight. The reaction masswas diluted with ethyl acetate and quenched with water. The aqueouslayer was extracted with ethyl acetate (10 ml×4). The organic layer wascombined, dried over anhydrous sodium sulphate, concentrated andpurified by column chromatography (50% ethyl acetate:PET ether) to givetitle compound. Yield: 0.115 g, 51.5%. ¹H NMR (300 MHz, DMSO-d₆) δ: 8.82(s, 1H), 8.66 (d, J=5.1 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.38-7.35 (d,J=8.4 Hz, 2H), 7.28 (m, 2H), 7.12-7.09 (d, J=8.4 Hz, 2H), 6.84-6.81 (d,J=8.7 Hz, 1H), 4.92 (s, 2H), 3.68 (s, 3H), 2.64-2.59 (m, 2H), 2.36-2.31(m, 2H), 1.99-1.89 (m, 2H), 1.82-1.78 (m, 2H), 1.49-1.45 (m, 2H); MS(E/Z): 427 (M+1)

Step 19e

Synthesis of4-(4-((4-(4-(1-cyanocyclopropyl)phenyl)pyridin-3-yl)methoxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((4-(4-(1-cyanocyclopropyl)phenyl)pyridin-3-yl)methoxy)phenyl)butanoate(0.100 g, 0.234 mM) with LiOH.H₂O (0.938 ml, 1.5M), according to generalprocedure D (as described herein above). Yield: 0.078 g, 81%; ¹H NMR(300 MHz, DMSO-d₆) δ: 8.79 (s, 1H), 8.65 (d, J=5.1 Hz, 1H), 7.46 (d,J=8.1 Hz, 2H), 7.37 (d, =8.1 Hz, 2H), 7.12-7.09 (d, J=8.4 Hz, 2H),6.83-6.80 (d, J=8.7 Hz, 2H), 4.91 (s, 2H), 2.66-2.61 (m, 2H), 2.39-2.34(m, 2H), 1.98-1.93 (m, 2H), 1.81-1.77 (m, 2H), 1.48-1.44 (m, 2H); MS(E/Z): 413 (M+1).

Example 203-(5-((2-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)pyridin-2-yl)propanoicacid

Step 20a

Synthesis of ethyl3-(5-((2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)pyridin-2-yl)propanoate

A mixture of (E)-ethyl3-(5-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)pyridin-2-yl)acrylate(0.150 g, 0.351 mM), 3-bromobicyclo[4.2.0]octa-1(6),2,4-triene (0.096 g,0.527 mM), K₂CO₃ (0.121 g, 0.878 mM) was dissolved in dioxane:water (8:2ml). The mixture was degassed using argon for 5 min. Triphenylphosphine(0.201 g, 0.246 mM) was added and the reaction mixture was degassed for5 min. Then, palladium salt (0.020 g) was added, and degassed forfurther for 5 min. The reaction was heated at 80° C. for 4 h, reactionwas monitored by TLC (20% ethyl acetate:PET ether). The dioxane wasremoved under high vacuum, diluted with water, aqueous layer wasextracted with ethyl acetate, dried over sodium sulfate and purifiedwith column chromatography to give the title compound. Yield: 0.097 g,0.240 mM, 68.5%. ¹H NMR (300 MHz, DMSO-d₆) δ: 8.30 (s, 1H), 7.70 (d,J=8.4, 1H), 7.62 (d, J=15.6 Hz, 1H), 7.46 (d, J=9.6 Hz, 1H), 7.36-7.27(m, 3H), 7.17-7.08 (m, 2H), 6.73 (d, J=15.6 Hz, 1H), 5.05 (s, 2H), 4.17(q, J=7.2 Hz, 2H), 3.13 (s, 4H), 1.25 (t, J=7.2 Hz, 3H); MS (E/Z): 404(M+1).

Step 20b

Synthesis of3-(5-((2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)pyridin-2-yl)propanoicacid

The title compound was prepared in an analogous manner as Example 2involving the reaction ofethyl-3-(5-((2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)pyridin-2-yl)propanoate(0.085 g, 0.210 mM) with LiOH.H₂O (0.839 ml, 1.5M), according to generalprocedure D (as described herein above). Yield: 54%; ¹H NMR (300 MHz,DMSO-d₆) δ: 12.08 (s, 1H), 8.11 (d, J=2.7 Hz, 1H), 7.43-7.39 (m, 1H),7.34-7.29 (m, 2H), 7.25-7.07 (m, 5H), 4.96 (s, 2H), 3.14 (s, 4H), 2.87(t, J=7.2 Hz, 2H), 2.58 (t, J=7.5 Hz, 2H); MS (E/Z): 378 (M+1).

Example 213-(4-((2-(4-(1-Cyanocyclopropyl)phenyl)pyridin-3-yl)methoxy)phenyl)propanoicacid

Step 21a

Synthesis of methyl 3-(4-((2-bromopyridin-3-yl)methoxy)phenyl)propanoate

A mixture of (2-bromopyridin-3-yl)methanol (0.500 g, 2.66 mM), methyl3-(4-hydroxyphenyl)propanoate (0.479 g, 2.66 mM), PPh₃ (0.697 g, 2.66mM) was dissolved in THF (5 ml), cooled to 0° C. (E)-diethyldiazene-1,2-dicarboxylate (0.463 g, 2.66 mM) was added slowly into thereaction mixture. The reaction mixture was stirred at RT for overnightand THF was removed under vacuum and then reaction mass was quenchedwith water. The aqueous layer was extracted by ethyl acetate, combinedthe organic layer, dried over Na₂SO₄, concentrated and purified bycolumn chromatography to give the title compound. Yield: 0.60 g, 64%; ¹H(DMSOd₆, 300 MHz): δ 8.36-8.34 (m, 1H), 7.95 (d, J=6 Hz, 1H), 7.49 (q,J=4.5 Hz, J=7.2 Hz, 1H), 7.16 (d, J=8.7 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H),5.07 (s, 2H), 3.56 (s, 3H), 2.77 (t, J=7.5 Hz, J=15 Hz, 2H), 2.55 (t,J=7.5 Hz, J=14.1 Hz, 2H). MS (e/z): 352 [M+2].

Step 21b

Synthesis of ethyl3-(4-((2-(4-(1-cyanocyclopropyl)phenyl)pyridin-3-yl)methoxy)phenyl)propanoate

Methyl 3-(4-((2-bromopyridin-3-yl)methoxy)phenyl)propanoate (0.150 g,0.428 mM) and (4-(1-cyanocyclopropyl)phenyl)boronic acid (0.096 g, 0.514mM) were dissolved in dioxane:water (4:1) and K₂CO₃ (0.148 g, 1.07 mM)was added into it. The reaction mixture was degassed under argon,followed by the addition of triphenylphosphine palladium salt (0.006 g,0.021 mM) and irradiated at 120° C. for 20 min in microwave. The dioxanewas removed under high vacuum, diluted with water, aqueous layer wasextracted with ethyl acetate, dried over sodium sulfate and purifiedwith column chromatography to give the title compound. Yield: 0.14 g,77%; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.66-8.65 (d, J=4.5 Hz, 1H), 8.12-8.00(m, 1H), 7.65-7.63 (m, 2H), 7.41-7.39 (m, 3H), 7.13-7.11 (m, 2H),6.85-6.83 (m, 2H), 5.01 (s, 2H), 3.57 (s, 3H), 2.77-2.75 (m, 2H),2.59-2.58 (m, 2H), 1.79 (s, 2H), 1.58 (s, 2H); MS (E/Z): 413 (M+1).

Step 21c

Synthesis of3-(4-((2-(4-(1-cyanocyclopropyl)phenyl)pyridin-3-yl)methoxy)phenyl)propanoicacid

The title compound was prepared in an analogous manner as Example 2involving the reaction ofethyl-3-(4-((2-(4-(1-cyanocyclopropyl)phenyl)pyridin-3-yl)methoxy)phenyl)propanoate(0.130 g, 0.315 mM) with LiOH.H₂O (1.261 ml, 1.5M) according to generalprocedure D (as described herein above). Yield: 88%; ¹H NMR (300 MHz,DMSO-d₆) δ: 12.08 (s, 1H), 8.67-8.66 (d, J=4.5 Hz, 1H), 7.65-7.64 (m,3H), 7.41-7.40 (m, 2H), 7.14-7.12 (m, 2H), 6.85-6.83 (m, 2H), 5.02 (s,2H), 2.74-2.72 (m, 2H), 2.50-2.48 (m, 2H), 1.79 (s, 2H), 1.58 (s, 2H);MS (E/Z): 378 (M+1), 399 (M+1).

Example 224-(4-((2-(2,3-Dihydrobenzofuran-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 22a

Synthesis of methyl4-(4-((2-(2,3-dihydrobenzofuran-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 12a ofExample 12 involving the reaction ofmethyl-4-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)butanoate (compound ofstep 1a of Example 1) (120 mg, 0.315 mM) with(2,3-dihydrobenzofuran-5-yl)boronic acid (103 mg, 0.630 mM), accordingto general procedure C (as described herein above). Yield: 90 mg, 0.206mM, 65.5%; ¹H NMR (300 MHz, CDCl₃) δ: 7.40-7.31 (m, 1H), 7.26-7.23 (m,1H), 7.15 (s, 1H), 7.07-7.01 (m, 4H), 6.82-6.77 (m, 3H), 4.89 (s, 2H),4.61 (t, J=8.7 Hz, 2H), 3.66 (s, 3H), 3.21 (t, J=8.7 Hz, 2H), 2.58 (t,J=7.2 Hz, 2H), 2.31 (t, J=7.5 Hz, 2H), 1.96-1.86 (m, 2H); MS (E/Z):443.2 (M+Na).

Step 22b

Synthesis of4-(4-((2-(2,3-Dihydrobenzofuran-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(2,3-dihydrobenzofuran-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoate(75 mg, 0.178 mM) with LiOH.H₂O (37.4 mg, 0.892 mM), according togeneral procedure D (as described herein above). Yield: 62 mg, 0.153 mM,86%; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.02 (bs, 1H), 7.38-7.29 (m, 2H),7.23-7.19 (m, 2H), 7.09-7.04 (m, 3H), 6.81-6.76 (m, 3H), 4.90 (s, 2H),4.53 (t, J=8.7 Hz, 2H), 3.14 (t, J=8.7 Hz, 2H), 2.44-2.48 (m, 2H), 2.16(t, J=7.2 Hz, 2H), 1.77-1.70 (m, 2H); MS (E/Z): 429.0 (M+Na).

Example 234-(4-((5-Fluoro-2-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)benzyl)oxy)phenyl)butanoicacid

Step 23a

Synthesis of methyl4-(4-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as Example 1involving the reaction of 2-bromo-4,5,6,7-tetrahydrobenzo[b]thiophene(73.0 g, 336 mM) withmethyl-4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(120 mg, 280 mM) and potassium carbonate (97 mg, 700 mM) in presence oftetrakis(triphenyl)phosphine palladium(0) (19.4 mg, 16.81 mM), accordingto general procedure C (as described herein above). Yield: 78.2 mg, 178mM, 63.5%; ¹H NMR (300 MHz, CDCl₃) δ: 7.42-7.32 (m, 2H), 7.10-7.00 (m,3H), 6.85 (d, J=8.4 Hz, 2H), 6.68 (s, 1H), 5.08 (s, 2H), 3.66 (s, 3H),2.78 (t, J=7.5 Hz, 2H), 2.59 (t, J=7.2 Hz, 4H), 2.32 (t, J=7.2 Hz, 2H),1.97-1.84 (m, 6H); MS (E/Z): 439.8 (M+H).

Step 23b

Synthesis of4-(4-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)benzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)benzyl)oxy)phenyl)butanoate(80 mg, 0.182 mM) with LiOH.H₂O (38.2 mg, 0.912 mM), according togeneral procedure D (as described herein above). Yield: 63.2 mg, 0.148mM, 81%; ¹H NMR (300 MHz, CDCl₃) δ: 12.04 (bs, 1H), 7.47-7.40 (m, 2H),7.27-7.24 (m, 1H), 7.10 (d, J=8.1 Hz, 2H), 6.88-6.84 (m, 3H), 5.04 (s,2H), 2.69 (t, J=7.5 Hz, 2H), 2.54-2.45 (m, 4H), 2.17 (t, J=7.2 Hz, 2H),1.78-1.68 (m, 6H); MS (E/Z): 425.1 (M+H), 422.9 (M−H).

Example 244-(4-((2-(6,7-Dihydro-5H-cyclopenta[b]pyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 24a

Synthesis of methyl4-(4-((2-(6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as Example 1involving the reaction of 3-bromo-6,7-dihydro-5H-cyclopenta[b]pyridine(78 mg, 0.395 mM) withmethyl-4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(130 mg, 0.304 mM) and potassium carbonate (105 mg, 0.759 mM) inpresence of tetrakis(triphenyl)phosphine palladium(0) (21.04 mg, 0.018mM) according to general procedure C (as described herein above). Yield:87.8 mg, 0.209 mM, 69.0%; ¹H NMR (300 MHz, CDCl₃) δ: 7.43-7.23 (m, 5H),7.55 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 4.90 (s, 2H), 3.66 (s,3H), 3.05 (t, J=7.8 Hz, 2H), 2.93 (t, J=7.2 Hz, 2H), 2.58 (t, J=7.5 Hz,2H), 2.31 (t, J=7.5 Hz, 2H), 2.20-2.15 (m, 2H), 1.93-1.88 (m, 2H); MS(E/Z): 420.5 (M+H).

Step 24b

Synthesis of4-(4-((2-(6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoate(47 mg, 0.112 mM) with LiOH.H₂O (23.5 mg, 0.560 mM), according togeneral procedure D (as described herein above). Yield: 40.4 mg, 0.099mM, 88%; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.03 (bs, 1H), 8.27 (s, 1H), 7.62(s, 1H), 7.47-7.26 (m, 3H), 7.06 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.7 Hz,2H), 4.89 (s, 2H), 2.92-2.83 (m, 4H), 2.16 (t, J=7.2 Hz, 2H), 2.07 (t,J=7.5 Hz, 2H), 2.10-2.02 (m, 2H), 1.74-1.69 (m, 2H); MS (E/Z): 406.5(M+H).

Example 254-(4-((5-Fluoro-2-(7-methylene-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoicacid

Step 25a

Synthesis of 2-bromo-7-methylene-4,5,6,7-tetrahydrobenzo[d]thiazole

To a stirred solution of 1,1′-biphenyl compound withbromo(methylene)(phenyl)phosphorane (1:1) (400 mg, 1.120 mM) dissolvedin dry THF (10 ml), n-butyllithium was added (646 μl, 1.034 mM) at −78°C. and allowed to stir for 30-40 min.2-bromo-5,6-dihydrobenzo[d]thiazol-7(4H)-one (200 mg, 0.862 mM) wasslowly added to the mixture and the mixture was allowed to stir at roomtemperature for 3-5 h. After completion of reaction, the mixture wasquenched with ammonium chloride, extracted with ethyl acetate,concentrated and purified by column chromatography to give the titlecompound. Yield: 120 mg, 0.521 mM, 60.5%; ¹H NMR (300 MHz, CDCl₃) δ:5.00 (s, 1H), 4.93 (s, 1H), 2.84 (t, J=6.3 Hz, 2H), 2.51-2.47 (m, 2H),1.96-1.88 (m, 2H); HPLC: 73.96%; MS (E/Z): 229.9 (M⁺).

Step 25b

Synthesis of methyl4-(4-((5-fluoro-2-(7-methylene-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as Example 1involving the reaction of2-bromo-7-methylene-4,5,6,7-tetrahydrobenzo[d]thiazole (56.4 mg, 0.245mM) with methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(70 mg, 0.163 mM) and potassium carbonate (70.6 mg, 0.511 mM) inpresence of tetrakis(triphenyl)phosphine palladium(0) (14.16 mg, 0.012mM), according to general procedure C (as described herein above).Yield: 62 mg, 0.135 mM, 66.0%; ¹H NMR (300 MHz, CDCl₃) δ: 7.73-7.68 (m,1H), 7.49-7.47 (m, 1H), 7.10-7.02 (m, 3H), 6.87 (d, J=8.7 Hz, 2H), 5.46(s, 2H), 5.13 (s, 1H), 4.95 (s, 1H), 3.66 (s, 3H), 2.89 (t, J=6.00 Hz,2H), 2.62-2.53 (m, 4H), 2.32 (t, J=7.5 Hz, 2H), 2.02-1.87 (m, 4H); MS(E/Z): 452.5 (M+H).

Step 25c

Synthesis of4-(4-((5-fluoro-2-(7-methylene-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction ofmethyl-4-(4-((5-fluoro-2-(7-methylene-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoate(55 mg, 0.122 mM) with LiOH.H₂O (25.6 mg, 0.183 mM), according togeneral procedure D (as described herein above). Yield: 40.4 mg, 0.099mM, 88%; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.02 (bs, 1H), 7.86-7.82 (m, 1H),7.50-7.47 (m, 1H), 7.34-7.29 (m, 1H), 7.09 (d, J=8.4 Hz, 2H), 6.85 (d,J=8.1 Hz, 2H), 5.41 (s, 2H), 5.01 (d, J=7.5 Hz, 2H), 2.76 (t, J=5.7 Hz,2H), 2.52-2.45 (m, 4H), 2.17 (t, J=7.2 Hz, 2H), 1.86-1.84 (m, 2H),1.78-1.71 (m, 2H); MS (E/Z): 438.3 (M+H).

Example 264-(4-((2-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)benzyl)oxy)phenyl)butanoicacid

Step 26a

Synthesis of methyl4-(4-((2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 12a ofExample 12 involving the reaction of methyl4-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)butanoate (compound of step 1aof Example 1) (100 mg, 0.275 mM) withbicyclo[4.2.0]octa-1(6),2,4-trien-3-ylboronic acid (61.1 mg, 0.413 mM),according to general procedure C (as described herein above). Yield: 85mg, 0.22 mM, 80%; ¹H NMR (300 MHz, CDCl₃) 7.60-7.63 (m, 1H), 7.33-7.40(m, 2H), 7.27-7.32 (m, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.06 (t, J=8.1 Hz,4H), 6.81 (d, J=8.7 Hz, 2H), 4.98 (s, 2H), 3.66 (s, 3H), 3.21 (s, 4H),2.60 (t, J=7.5 Hz, 2H), 2.34 (t, J=7.5 Hz, 2H), 1.89-1.96 (m, 2H); MSm/z 387.3 [M+1].

Step 26b

Synthesis of4-(4-((2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)benzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)benzyl)oxy)phenyl)butanoate(80 mg, 0.207 mM) with LiOH.H₂O (43.4 mg, 1.03 mM), according to generalprocedure D (as described herein above). Yield: 55 mg, 0.148 mM, 71.3%;¹H NMR (300 MHz, DMSO-d₆) δ 12.03 (s, 1H), 7.54-7.57 (m, 1H), 7.40 (t,J=3.9 Hz, 2H), 7.24-7.27 (m, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.03-7.10 (m,4H), 6.79 (d, J=7.8 Hz, 2H), 4.88 (s, 2H), 3.13 (s, 4H), 2.48 (m, 2H),2.16 (t, J=7.2 Hz, 2H), 1.69-1.76 (m, 2H); MS, m/z 370.8 [M−1].

Example 274-(4-((2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid

Step 27a

Synthesis of methyl4-(4-((2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 12a ofExample 12 involving the reaction of methyl4-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)butanoate (compound of step 1aof Example 1) (100 mg, 0.275 mM) with(5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid (72.7 mg, 0.413 mM),according to general procedure C (as described herein above). Yield: 95mg, 0.229 mM, 83%; ¹H NMR (300 MHz, CDCl₃) δ 7.59-7.60 (m, 1H),7.32-7.39 (m, 3H), 7.04-7.13 (m, 5H), 6.83 (d, J=8.4 Hz, 2H), 4.93 (s,2H), 3.66 (s, 3H), 2.72 (m, 4H), 2.58 (t, J=7.8 Hz, 2H), 2.31 (t, J=7.8Hz, 2H), 1.86-1.96 (m, 2H), 1.77-1.81 (m, 4H); MS m/z 437.0 [M+Na⁺]

Step 27b

Synthesis of4-(4-((2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction ofmethyl-4-(4-((2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoate[90 mg, 0.217 m mol] with LiOH.H₂O [46 mg, 1.08 mM], according togeneral procedure D (as described herein above). Yield: 60 mg, 0.150 mmol, 69.0%; ¹H NMR (300 MHz, DMSO-d₆) δ 12.03 (s, 1H), 7.55-7.57 (m,1H), 7.30-7.39 (m, 3H), 7.04-7.07 (m, 5H), 6.81 (d, J=8.4 Hz, 2H), 4.88(s, 2H), 2.60-2.70 (m, 4H), 2.47-2.49 (m, 2H), 2.16 (t, J=7.2 Hz, 2H),1.69-1.72 (m, 6H); MS m/z 398.8 [M−1].

Example 284-(4-((2-(5-Cyclobutylthiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 28a

Synthesis of methyl4-(4-((2-(5-cyclobutylthiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzyl)oxy)phenyl)butanoate(compound of step 1a of Example 1) [100 mg, 0.232 mM] with2-bromo-5-cyclobutylthiophene [76 mg, 0.348 mM] according to generalprocedure C (as described herein above). Yield: 40 mg, 0.091 mM, 39.3%;¹H NMR (CDCl₃, 300 MHz) δ 7.32-7.44 (m, 2H), 7.01-7.10 (m, 3H),6.83-6.87 (m, 3H), 6.76 (d, J=3.3 Hz, 1H), 5.06 (s, 2H), 3.66 (s, 3H),2.59 (t, J=7.5 Hz, 2H), 2.41-2.44 (m, 2H), 2.20 (t, J=9.3 Hz, 2H),2.14-2.16 (m, 2H), 2.01-2.04 (m, 2H), 1.90-1.98 (m, 3H); MS m/z 439.0[M+1].

Step 28b

Synthesis of4-(4-((2-(5-cyclobutylthiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(5-cyclobutylthiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate[40 mg, 0.091 mM] with LiOH.H₂O [19.14 mg, 0.45 mM], according togeneral procedure D (as described herein above). Yield: 20 mg, 0.047 mM,51.7%; ¹H NMR (DMSO d₆, 300 MHz) δ 12.02 (s, 1H), 7.42-7.51 (m, 2H),7.23-7.29 (m, 1H), 7.10 (d, J=8.4 Hz, 2H), 7.08 (d, J=3.6 Hz, 1H),6.84-6.88 (m, 3H), 5.02 (s, 2H), 3.64-3.70 (m, 1H), 2.48 (m, 2H),2.32-2.35 (m, 2H), 2.15-2.20 (t, J=7.2 Hz, 2H), 1.71-1.97 (m, 4H),1.16-1.22 (m, 2H); MS m/z 446.8 [M+Na⁺].

Example 294-(4-((4′-cyclopropyl-4-fluoro-3′-methyl-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid

Step 29a

Synthesis of methyl4-(4-((4′-cyclopropyl-4-fluoro-3′-methyl-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzyl)oxy)phenyl)butanoate(compound of step 1a of Example 1) [100 mg, 0.232 mM] with4-bromo-1-cyclopropyl-2-methylbenzene [73.9 mg, 0.350 mM] according togeneral procedure C (as described herein above). Yield: 55 mg, 0.127 mM,54.5%; ¹H NMR (300 MHz, CDCl₃) δ: 7.35 (d, J=7.2 Hz, 1H), 6.90-7.18 (m,7H), 6.79 (d, J=8.7 Hz, 2H), 4.90 (s, 2H), 3.36 (s, 3H), 2.60 (t, J=7.5Hz, 2H), 2.42 (s, 3H), 2.28-2.36 (m, 3H), 1.88-1.96 (m, 2H), 0.93-0.99(m, 2H), 0.67-0.70 (m, 2H); MS m/z 433.4 [M+1].

Step 29b

4-(4-((4′-cyclopropyl-4-fluoro-3′-methyl-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((4′-cyclopropyl-4-fluoro-3′-methyl-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoate[50 mg, 0.116 mM] with LiOH.H₂O [24.2 mg, 0.578 mM] according to generalprocedure D (as described herein above). Yield: 15 mg, 0.036 mM, 31.0%;¹H NMR (300 MHz, DMSO-d₆) δ: 12.02 (s, 1H), 7.27-7.40 (m, 2H), 6.93-7.16(m, 4H), 6.93-6.96 (d, J=8.1 Hz, 2H), 6.77-6.80 (d, J=8.4 Hz, 2H), 4.88(s, 2H), 3.32 (s, 3H), 2.32 (s, 2H), 2.16 (t, J=7.2 Hz, 2H), 1.89 (m,1H), 1.72-1.74 (m, 2H), 0.86-0.92 (m, 2H), 0.60-0.61 (m, 2H); MS m/z416.9 [M−1].

Example 304-(4-((2-(6-Cyclopropylpyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 30a

Synthesis of methyl4-(4-((2-(6-cyclopropylpyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzyl)oxy)phenyl)butanoate(compound of step 1a of Example 1) [100 mg, 0.232 mM] with5-bromo-2-cyclopropylpyridine [69.4 mg, 0.350 mM], according to generalprocedure C (as described herein above). Yield: 55 mg, 0.131 m mol,56.2%; ¹H NMR (300 MHz, CDCl₃) δ: 8.42 (s, 1H), 7.56 (d, J=7.8 Hz, 1H),7.35 (d, J=9.6 Hz, 1H), 7.00-7.17 (m, 5H), 6.76 (d, J=8.4 Hz, 2H), 4.87(s, 2H), 3.67 (s, 3H), 2.61 (t, J=7.2 Hz, 2H), 2.34 (t, J=7.2 Hz, 2H),2.08-2.10 (m, 1H), 1.89-1.94 (m, 2H), 1.05 (d, J=8.1 Hz, 4H); MS m/z420.5 [M+1].

Step 30b

Synthesis of4-(4-((2-(6-cyclopropylpyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(6-cyclopropylpyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoate[50 mg, 0.119 mM] with LiOH.H₂O [25 mg, 0.59 mM], according to generalprocedure D (as described herein above). Yield: 30 mg, 0.074 mM, 62.1%;¹H NMR (DMSO d₆, 300 MHz) δ: 11.94 (s, 1H), 8.55 (s, 1H), 7.33-7.50 (m,3H), 6.98-7.07 (m, 3H), 6.79 (d, J=8.1 Hz, 2H), 6.72 (d, J=8.1 Hz, 1H),4.95 (s, 2H), 2.26 (s, 1H), 2.15-2.17 (m, 3H), 1.70-1.75 (m, 3H),1.05-1.15 (m, 4H); MS, m/z 407.4 [M+2].

Example 314-(4-((2-(2-Cyclopropylpyrimidin-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 31a

Synthesis of methyl4-(4-((2-(2-cyclopropylpyrimidin-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzyl)oxy)phenyl)butanoate(compound of step 1a of Example 1) [100 mg, 0.232 m mol] with5-bromo-2-cyclopropylpyrimidine (69.7 mg, 0.350 mM), according togeneral procedure C (as described herein above). Yield: 55 mg, 0.131 mM,56.0%; ¹H NMR (300 MHz, CDCl₃) δ: 8.58 (s, 2H), 7.40 (d, J=6.9 Hz, 1H),7.06-7.23 (m, 2H), 7.13 (d, J=8.4 Hz, 2H), 6.79 (d, J=8.4 Hz, 2H), 4.85(s, 2H), 3.67 (s, 3H), 2.61 (t, J=7.5 Hz, 2H), 2.26-2.34 (m, 3H),1.86-1.96 (m, 2H), 1.11-1.17 (m, 4H); MS m/z 421.5 [M+1].

Step 31b

Synthesis of4-(4-((2-(2-cyclopropylpyrimidin-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction ofmethyl-4-(4-((2-(2-cyclopropylpyrimidin-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoate[50 mg, 0.119 mM] with LiOH.H₂O [25 mg, 0.59 mM], according to generalprocedure D (as described herein above). Yield: 32 mg, 0.079 mM, 66.2%;¹H NMR (300 MHz, DMSO-d₆) δ: 12.02 (s, 1H), 8.66 (s, 2H), 7.33-7.51 (m,3H), 7.05-7.07 (d, J=7.8 Hz. 2H), 6.81 (d, J=8.1 Hz, 2H), 4.94 (s, 2H),2.49 (m, 2H), 2.15-2.17 (m, 3H), 1.70-1.75 (m, 2H), 0.99-1.03 (m, 4H);MS m/z 406.6 [M⁺].

Example 324-(4-((2-(4-Cyclopropylthiazol-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 32a

Synthesis of methyl4-(4-((2-(4-cyclopropylthiazol-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzyl)oxy)phenyl)butanoate(compound of step 1a of Example 1) [100 mg, 0.232 mM] with5-bromo-4-cyclopropylthiazole (71.5 mg, 0.350 mM), according to generalprocedure C (as described herein above). Yield: 57 mg, 0.134 mM, 57.4%;¹H NMR (300 MHz, CDCl₃) δ: 7.62-7.65 (m, 1H), 7.47-7.55 (m, 2H),7.01-7.10 (m, 3H), 6.89 (d, J=8.4 Hz, 2H), 5.42 (s, 2H), 3.67 (s, 3H),2.61 (t, J=7.2 Hz, 2H), 2.34 (t, J=7.5 Hz, 2H), 2.05-2.12 (m, 1H),1.87-1.97 (m, 2H), 1.05-1.21 (m, 2H), 0.76-0.81 (m, 2H); LCMS m/z 425.9[M+1].

Step 32b

Synthesis of4-(4-((2-(4-cyclopropylthiazol-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(4-cyclopropylthiazol-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoate[50 mg, 0.118 m mol] with LiOH.H₂O [24.6 mg, 0.58 mM], according togeneral procedure D (as described herein above). Yield: 20 mg, 0.049 mM,41.4%; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.02 (s, 1H), 8.97 (s, 1H),7.45-7.45 (m, 1H), 7.30-7.31 (m, 2H), 6.98-7.07 (m, 2H), 6.79 (d, J=8.1Hz, 1H), 6.72 (d, J=8.1 Hz, 1H), 4.90 (s, 2H), 2.49 (m, 2H), 2.14-2.16(m, 2H), 1.69-1.745 (m, 3H), 0.87-1.23 (m, 4H); MS m/z 412.5 [M+1].

Example 334-(4-((2-(2,3-Dihydro-1H-inden-5-yl)benzyl)oxy)phenyl)butanoic acid

Step 33a

Synthesis of methyl4-(4-((2-(2,3-dihydro-1H-inden-5-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 12a ofExample 12 involving the reaction ofmethyl-4-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)butanoate (compound ofstep 1a of Example 1) (70 mg, 0.171 mM) with(2,3-dihydro-1H-inden-5-yl)boronic acid (50.4 mg, 0.256 mM), accordingto general procedure C (as described herein above). Yield: 45 mg, 0.112mM, 65.9%; ¹H NMR (CDCl₃, 300 MHz) δ: 7.59-7.62 (m, 1H), 7.31-7.39 (m,3H), 7.23-7.26 (m, 2H), 7.16 (d, J=8.1 Hz, 1H), 7.06 (d, J=8.1 Hz, 2H),6.81 (d, J=8.1 Hz, 2H), 4.93 (s, 2H), 3.66 (s, 3H), 2.87-2.96 (m, 4H),2.57 (t, J=7.5 Hz, 2H), 2.31 (t, J=7.5 Hz, 2H), 2.02-2.15 (m, 2H),1.86-1.96 (m, 2H); MS m/z: 423.2 [M+Na].

Step 33b

Synthesis of4-(4-((2-(2,3-dihydro-1H-inden-5-yl)benzyl)oxy)phenyl)butanoic acid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(2,3-dihydro-1H-inden-5-yl)benzyl)oxy)phenyl)butanoate [40 mg,0.100 mM] with LiOH.H₂O (20.96 mg, 0.499 mM), according to generalprocedure D (as described herein above). Yield: 25 mg, 0.065 mM, 64.8%;¹H NMR (DMSO d₆, 300 MHz) δ 12.01 (s, 1H), 7.54-7.57 (m, 1H), 7.38-7.39(m, 2H), 7.23-7.30 (m, 3H), 7.14 (d, J=7.8 Hz, 1H), 7.06 (d, J=8.4 Hz,2H), 6.79 (d, J=8.4 Hz, 2H), 4.87 (s, 2H), 2.87 (m, 4H), 2.49 (m, 2H),2.18 (t, J=7.2 Hz, 2H), 1.89-2.02 (m, 2H), 1.16-1.38 (m, 2H); MS m/z409.0 [M+Na].

Example 344-(4-((5-Fluoro-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid

Step 34a

Synthesis of methyl4-(4-((5-fluoro-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the general procedure C (as described herein above),methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(150 mg, 0.35 mM) was coupled with6-bromo-3,4-dihydronaphthalen-1(2H)-one (92 mg, 0.44 mM). Yield: 102 mg,51.93%; ¹H NMR (CDCl₃, 500 MHz): δ 8.07 (d, J=8.1 Hz, 1H), 7.39-7.35 (m,1H), 7.31-7.28 (m, 2H), 7.26-7.24 (m, 1H), 7.13-7.04 (m, 3H) 6.78 (d,J=8.7 Hz, 2H), 4.86 (s, 2H), 3.66 (s, 3H), 2.92 (t, J=5.7, 6.0 Hz, 2H),2.68 (t, J=6.9 Hz, 2H), 2.58 (t, J=7.8 Hz, 2H), 2.31 (t, J=7.5 Hz, 2H),2.18-2.13 (m, 2H), 1.96-1.86 (m, 2H); MS (m/z): 469.2 [M+Na].

Step 34b

Synthesis of4-(4-((5-fluoro-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((5-fluoro-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoate(95 mg, 0.21 mM) with LiOH.H₂O (44.6 mg, 1.06 mM), according to generalprocedure D (as described herein above). Yield: 80 mg, 86.9%; ¹H NMR(300 MHz, DMSO-d₆): δ 12.10 (br, m, 1H), 7.87 (d, J=8.7 Hz, 1H),7.47-7.27 (m, 5H), 7.06 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H), 4.90(s, 2H), 2.85 (t, J=5.4, 5.7 Hz, 2H), 2.58 (t, J=6.0, 6.3 Hz, 2H),2.48-2.45 (m, 2H), 2.15 (t, J=7.2, 7.5 Hz, 2H), 2.02-1.97 (m, 2H),1.76-1.69 (m, 2H); MS (m/z) 455.1 [M+Na].

Example 354-(4-((2-(7,8-Dihydronaphthalen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 35a

Synthesis of methyl4-(4-((2-(7,8-dihydronaphthalen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the general procedure C (as described herein above)by using methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(150 mg, 0.35 mM) with 7-bromo-1,2-dihydronaphthalene (49 mg, 0.23 mM).Yield: 51 mg, 50.8%; ¹H NMR (300 MHz, CDCl₃): δ 7.37 (d, J=9.5 Hz, 1H),7.31-7.28 (m, 1H), 7.14 (d, J=7.5 Hz, 1H), 7.09-7.06 (m, 5H), 6.81 (d,J=8.5 Hz, 2H), 6.52 (d, J=8.5 Hz, 1H), 6.09-6.06 (m, 1H), 4.93 (s, 2H),3.67 (s, 3H), 2.79 (t, J=8.0 Hz, 2H), 2.59 (t, J=7.5 Hz, 2H), 2.34-2.31(m, 4H), 1.95-1.89 (m, 2H), MS (m/z) 453.2 [M+Na].

Step 35b

Synthesis of4-(4-((2-(7,8-dihydronaphthalen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(7,8-dihydronaphthalen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate(45 mg, 0.10 mM) with LiOH.H₂O (21.9 mg, 0.52 mM), according to generalprocedure D (as described herein above). Yield: 35 mg, 80.4%; ¹H NMR(500 MHz, DMSO-d₆): δ 12.03 (br, m, 1H), 7.43-7.36 (m, 2H), 7.28-7.25(m, 1H), 7.18-7.14 (m, 2H), 7.09-7.06 (m, 3H), 6.82 (d, J=8.0 Hz, 2H),6.52 (d, J=9.5 Hz, 1H), 6.07-6.05 (m, 1H), 4.91 (s, 2H), 2.68 (t, J=8.5,8.0 Hz, 2H), 2.47-2.50 (m, 2H), 2.23-2.24 (m, 2H), 2.17 (t, J=7.0, 7.5Hz, 2H), 1.75-1.72 (m, 2H); MS (m/z) 439.2 [M+Na].

Example 364-(4-((5-Fluoro-2-(5-methylene-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid

Step 36a

Synthesis of methyl4-(4-((5-fluoro-2-(5-methylene-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(150 mg, 0.35 mM) with 6-bromo-1-methylene-1,2,3,4-tetrahydronaphthalene(51 mg, 0.23 mM), general procedure C (as described herein above).Yield: 90 mg, 89.0%); ¹H NMR (500 MHz, CDCl₃): δ 7.70 (d, J=8.5 Hz, 1H),7.37 (d, J=9.5 Hz, 1H), 7.31-7.28 (m, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.08(t, J=8.0 Hz, 4H), 6.81 (d, J=8.0 Hz, 2H), 5.57 (s, 1H), 5.01 (s, 1H),4.93 (s, 2H), 3.67 (s, 3H), 2.83 (t, J=6.0 Hz, 2H), 2.61-2.58 (m, 4H),2.32 (t, J=7.5 Hz, 2H), 1.95-1.89 (m, 4H); MS (m/z) 445.2 [M+H].

Step 36b

Synthesis of4-(4-((5-fluoro-2-(5-methylene-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((5-fluoro-2-(5-methylene-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoate(80 mg, 0.18 mM) with LiOH.H₂O (37.7 mg, 0.89 mM), according to generalprocedure D (as described herein above). Yield: 65 mg, 83.9%; ¹H NMR(500 MHz, DMSO-d₆): δ 12.03 (br m, 1H), 7.71 (d, J=8.0 Hz, 1H),7.43-7.36 (m, 2H), 7.29-7.26 (m, 1H), 7.20-7.11 (m, 2H), 7.08 (d, J=8.5Hz, 2H), 6.83 (d, J=8.0 Hz, 2H), 5.57 (s, 1H), 4.98 (s, 1H), 4.91 (s,2H), 2.72 (t, J=6.0 Hz, 2H), 2.47-2.50 (m, 4H), 2.17 (t, J=7.0, 7.5 Hz,2H), 1.76-1.72 (m, 4H); MS (m/z) 431.2 [M+H].

Example 374-(4-(5-Fluoro-2-(5-methyl-7,8-dihydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid

Step 37a

Synthesis of 6-bromo-1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol

To a stirred solution of 6-bromo-3,4-dihydronaphthalen-1(2H)-one (200mg, 0.89 mM) in THF (5 ml) at 0° C., MeMgBr (954 mg, 8.0 mM) was addedand the reaction mixture was allowed to stir at RT for 5 h. The reactionmixture was quenched with saturated ammonium chloride solution,extracted with ethyl acetate, dried over anhydrous sodium sulphate andconcentrated. It was further purified to give the title compound. Yield:51.3%; ¹H NMR (DMSO, 300 MHz): δ 7.46 (d, J=8.4 Hz, 1H), 7.32-7.29 (m,1H), 7.23 (s, 1H), 4.94 (s, 1H), 2.68-2.66 (m, 2H), 1.78-1.67 (m, 4H),1.34 (s, 3H); MS (e/z): 242.1 [M+H].

Step 37b

Synthesis of 7-bromo-4-methyl-1,2-dihydronaphthalene

To a stirred solution of6-bromo-1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol (110 mg, 0.45 mM) inbenzene (5 ml), PTSA (3.47 mg, 0.018 mM) was added and the reactionmixture was allowed to reflux for 1.5 h with azeotropic removal of waterusing Dean-Stark apparatus. The reaction mixture was cooled to RT, thenwater (4.5 ml) was added, organic layer was separated washed withsaturated sodium bicarbonate solution, dried over anhydrous sodiumsulphate and concentrated. It was further purified to give the titlecompound. Yield: 80 mg, 78.66%; ¹H NMR (CDCl₃, 300 MHz): δ 7.33-7.30 (m,2H), 7.09 (d, J=8.4 Hz, 1H), 5.86-5.87 (m, 1H), 2.74 (t, J=7.8 Hz, 2H),2.24-2.18 (m, 2H), 2.03 (d, J=1.5 Hz, 3H); MS (e/z) 246.6 [M+Na].

Step 37c

Synthesis of methyl4-(4-((5-fluoro-2-(5-methyl-7,8-dihydronaphthalene-2-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(115 mg, 0.27 mM) with 7-bromo-4-methyl-1,2-dihydronaphthalene (40 mg,0.18 mM) as per the general procedure C (as described herein above).Yield: 55 mg (69.0%); ¹H NMR (300 MHz, CDCl₃): δ 7.37-7.29 (m, 2H),7.27-7.24 (m, 1H), 7.18-7.16 (m, 1H), 7.11-7.04 (m, 4H), 6.81 (d, J=8.4Hz, 2H), 5.88-5.89 (m, 1H), 4.93 (s, 2H), 3.66 (s, 3H), 2.74 (t, J=8.1Hz, 2H), 2.58 (t, J=7.5 Hz, 2H), 2.33-2.28 (m, 4H), 2.08 (s, 3H),1.96-1.88 (m, 2H); MS (m/z) 445.2 [M+H].

Step 37d

Synthesis of4-(4-((5-fluoro-2-(5-methyl-7,8-dihydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((5-fluoro-2-(5-methyl-7,8-dihydronaphthalene-2-yl)benzyl)oxy)phenyl)butanoate(50 mg, 0.11 mM) with LiOH.H₂O (23.6 mg, 0.56 mM), according to generalprocedure D (as described herein above). Yield: 44 mg, 90.9%; ¹H NMR(300 MHz, DMSO-d₆): δ 12.03 (br m, 1H), 7.43-7.35 (m, 2H), 7.29-7.22 (m,3H), 7.17 (s, 1H), 7.07 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H),5.85-5.86 (m, 1H), 4.90 (s, 2H), 2.62 (t, J=7.8, 8.1 Hz, 2H), 2.47-2.52(m, 2H), 2.16 (t, J=7.2 Hz, 4H), 2.00 (s, 3H), 1.77-1.69 (m, 2H); MS(m/z) 431.2 [M+H].

Example 384-(4-((5-Fluoro-2-(5-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid

Step 38a

Synthesis of 6-bromo-1-methoxy-1,2,3,4-tetrahydronaphthalene

To a stirred suspension of NaH (11.51 mg, 0.480 mM) (60% in mineral oil)in THF (3 ml) at 0° C., 6-bromo-1,2,3,4-tetrahydronaphthalen-1-ol (90mg, 0.396 mM) in THF (3 ml) was added and the reaction mixture wasallowed to stir at 0° C. for 30 min. Then, MeI (0.030 ml, 0.480 mM) wasadded and the reaction mixture was allowed to stir at 0° C. for 1 h andRT for 2 h. After the completion of the reaction, the reaction mixturewas quenched with ice cubes and concentrated. It was dissolved in ethylacetate and washed with water dried over anhydrous sodium sulphate andconcentrated. It was further purified to give the title compound. Yield:70 mg, 73.29%; ¹H NMR (CDCl₃, 300 MHz): δ 7.31-7.28 (m, 1H), 7.26-7.21(m, 2H), 4.26 (t, J=4.2 Hz, 1H), 3.43 (s, 3H), 2.83-2.63 (m, 2H),2.02-1.82 (m, 3H), 1.76-1.69 (m, 1H). MS (e/z): 242.1 [M+H].

Step 38b

Synthesis of methyl4-(4-((5-fluoro-2-(5-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(213 mg, 0.49 mM) with 6-bromo-1-methoxy-1,2,3,4-tetrahydronaphthalene(80 mg, 0.33 mM). Yield: 90 mg, 58.6%. ¹H NMR (300 MHz, CDCl₃): δ7.41-7.32 (m, 2H), 7.25-7.23 (m, 1H), 7.16-7.14 (m, 1H), 7.07-7.04 (m,4H), 6.79 (d, J=8.7 Hz, 2H), 4.90 (s, 2H), 4.33-4.35 (m, 1H), 3.66 (s,3H), 3.48 (s, 3H), 2.83-2.69 (m, 2H), 2.57 (t, J=7.5 Hz, 2H), 2.31 (t,J=7.5 Hz, 2H), 2.01-1.95 (m, 2H), 1.93-1.86 (m, 3H), 1.77-1.73 (m, 1H);MS (m/z) 485.5 [M+Na].

Step 38c

Synthesis of4-(4-((5-fluoro-2-(5-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction ofmethyl-4-(4-((5-fluoro-2-(5-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoate(80 mg, 0.16 mM) with LiOH.H₂O (36.3 mg, 0.86 mM), according to generalprocedure D (as described herein above). Yield: 63 mg, 81.2%; ¹H NMR(300 MHz, DMSO-d₆) δ: 12.03 (br m, 1H), 7.42-7.22 (m, 4H), 7.17-7.15 (m,1H), 7.09-7.04 (m, 3H), 6.81 (d, J=8.4 Hz, 2H), 4.87 (s, 2H), 4.25-4.26(m, 1H), 3.32 (s, 3H), 2.63-2.59 (m, 2H), 2.48-2.45 (m, 2H), 2.15 (t,J=7.2, 7.5 Hz, 2H), 1.89-1.63 (m, 6H); MS (m/z) 471.1 [M+Na].

Example 394-(4-((5-Fluoro-2-(5-methoxy-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid

Step 39a

Synthesis of 6-bromo-1-methoxy-1-methyl-1,2,3,4-tetrahydronaphthalene

To a stirred suspension of NaH (11.94 mg, 0.498 mM) in dry THF (5 ml) at0° C. under nitrogen was added6-bromo-1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol (100 mg, 0.415 mM) inTHF and the reaction mixture was allowed to stir at 0° C. for 0.5 h.Then MeI (0.031 ml, 0.498 mM) was added dropwise and the reactionmixture was allowed to stir at RT for 2 h. After the completion of thereaction, the reaction mixture was quenched with ice-cubes andconcentrated, extracted with ethyl acetate and washed with water, brinedried over anhydrous sodium sulphate and concentrated. Then it waspurified to give the title compound. Yield: 41 mg 38.75%; ¹H NMR (CDCl₃,300 MHz): δ 7.31-7.32 (m, 2H), 7.23 (s, 1H), 3.06 (s, 3H), 2.83-2.66 (m,2H), 2.16-2.08 (m, 1H), 1.95-1.92 (m, 1H), 1.85-1.70 (m, 2H), 1.46 (s,3H); MS (e/z): 254.1 [M−H].

Step 39b

Synthesis of methyl4-(4-((5-fluoro-2-(5-methoxy-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(88 mg, 0.20 mM) with6-bromo-1-methoxy-1-methyl-1,2,3,4-tetrahydronaphthalene (35 mg, 0.14mM). Yield: 48 mg, 72.9%; ¹H NMR (CDCl₃, 300 MHz): δ 7.49 (d, J=7.8 Hz,1H), 7.36-7.27 (m, 2H), 7.17-7.14 (m, 1H), 7.09-7.04 (m, 4H), 6.79 (d,J=8.7 Hz, 2H), 4.92 (s, 2H), 3.66 (s, 3H), 3.12 (s, 3H), 2.76-2.71 (m,2H), 2.58 (t, J=7.8 Hz, 2H), 2.31 (t, J=7.5 Hz, 2H), 2.20-2.16 (m, 1H),1.96-1.86 (m, 3H), 1.79-1.76 (m, 2H), 1.53 (s, 3H); MS (m/z) 499.6[M+Na].

Step 39c

Synthesis of4-(4-((5-fluoro-2-(5-methoxy-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((5-fluoro-2-(5-methoxy-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoate(40 mg, 0.084 mM) with LiOH.H₂O 17.5 mg, 0.41 mM), according to generalprocedure D (as described herein above), to give4-(4-((5-fluoro-2-(5-methoxy-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid. Yield: 32 mg, 82.4%; ¹H NMR (500 MHz, DMSO-d₆) δ 11.88 (br m, 1H),7.42-7.36 (m, 3H), 7.28-7.25 (m, 1H), 7.21 (d, J=7.5 Hz, 1H), 7.09 (s,1H), 7.07 (d, T=8.5 Hz, 2H), 6.79 (d, J=8.5 Hz, 2H), 4.90 (s, 2H), 2.94(s, 3H), 2.65-2.58 (m, 2H), 2.50-2.48 (m, 2H), 2.17 (t, J=7.5 Hz, 2H),2.07-2.02 (m, 1H), 1.83-1.85 (m, 1H), 1.76-1.70 (m, 3H), 1.66-1.62 (m,1H), 1.40 (s, 3H); MS (m/z): 485.5 [M+Na].

Example 404-(4-((5-Fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoicacid

Step 40a

Synthesis of 2-bromo-5-(prop-1-en-2-yl)thiophene

To a stirred suspension of methyltriphenylphosphonium bromide (6.27 g,17.55 mM) in THF (60 ml) at −78° C., n-butyllithium (10.97 ml, 17.55 mM)was added dropwise. The reaction mixture was allow to stir at RT for 2h, then a solution of 1-(5-bromothiophen-2-yl)ethanone (3.0 g, 14.63 mM)in THF was added and allowed for stirring for overnight. The reactionmixture was quenched with saturated ammonium chloride solution extractedwith ethyl acetate, organic layer was washed with brine solution, dried,concentrated and purified by column to give the title compound. Yield:2.1 g, 10.34 mM, 70.7%; ¹H NMR (CDCl₃, 500 MHz) δ 6.94 (d, J=4.0 Hz,1H), 6.78 (d, J=3.5 Hz, 1H), 5.29 (s, 1H), 4.97 (s, 1H), 2.11 (s, 3H);MS (e/z) 204.1 [M+H].

Step 40b

Synthesis of 2-bromo-5-(1-methylcyclopropyl)thiophene

To a stirred solution of diethylzinc (6.40 ml, 6.40 mM) in DCM at 0° C.,TFA (0.493 ml, 6.40 mM) was slowly added and the mixture was allowed tostir for 20 min. Then, diiodomethane (0.516 ml, 6.40 mM) was added andstirred for 20 min. A solution of 2-bromo-5-(prop-1-en-2-yl)thiophene(0.650 g, 3.20 mM) in DCM was added and the reaction mixture was stirredfor overnight. Then, the reaction mixture was washed with saturatedsodium bicarbonate solution, brine solution, dried over Na₂SO₄,concentrated and purified to give the title compound. Yield: 0.564 g,2.60 mM, 81%; ¹H NMR (CDCl₃, 300 MHz) δ 6.81 (d, J=3.90 Hz, 1H), 6.51(d, J=3.6 Hz, 1H), 1.43 (s, 3H), 0.87-0.92 (m, 2H), 0.79-0.84 (m, 2H).

Step 40c

Synthesis of methyl4-(4-((5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of2-bromo-5-(1-methylcyclopropyl)thiophene (0.051 g, 0.235 mM), methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(0.150 g, 0.350 mM), and K₂CO₃ (0.097 g, 0.700 mM) in presence oftetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.012 mM) accordingto general procedure C (as described herein above). Yield: 0.084 g,0.192 mM, 82%; ¹H NMR (CDCl₃, 300 MHz) δ 7.32-7.42 (m, 2H), 7.03-7.10(m, 3H), 6.82-6.85 (m, 3H), 6.70 (d, J=3.3 Hz, 1H), 5.05 (s, 2H), 3.66(s, 3H), 2.59 (t, J=7.2 Hz, 2H), 2.32 (t, J=7.5 Hz, 2H), 1.90-1.95 (m,2H), 1.49 (s, 3H), 0.90-1.00 (m, 2H), 0.80-0.90 (m, 2H); MS m/z 438.4[M⁺].

Step 40d

Synthesis of4-(4-((5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoate(0.075 g, 0.171 mM) with LiOH.H₂O (0.036 g, 0.855 mM), according togeneral procedure D (as described herein above). Yield: 0.056 g, 0.132mM, 77%; ¹H NMR (300 MHz, DMSO-d₆) δ 12.03 (s, 1H), 7.40-7.52 (m, 2H),7.20-7.30 (m, 1H), 7.09 (d, J=8.1 Hz, 2H), 6.96 (bs, 1H), 6.8 (d, J=8.4Hz, 2H), 6.79 (d, J=3.6 Hz, 1H), 5.01 (s, 2H), 2.40-2.55 (m, 2H), 2.18(t, J=7.2 Hz, 2H), 1.71-1.76 (m, 2H), 1.40 (s, 3H), 0.86 (s, 4H); MS:m/z 425.5 [M+H⁺].

Example 414-(4-((5-Fluoro-2-(5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoicacid

Step 41a

Synthesis of methyl4-(4-((5-fluoro-2-(5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of2-bromo-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazole (0.072 g, 0.311 mM),methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(0.200 g, 0.467 mM), K₂CO₃ (0.129 g, 0.934 mM), in presence oftetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.016 mM) accordingto general procedure C (as described herein above). Yield: 0.106 g,0.234 mM, 75%; ¹H NMR (500 MHz, CDCl₃) δ 7.63-7.66 (m, 1H), 7.46 (d,J=10.0 Hz, 1H), 7.10 (d, J=8.5 Hz, 2H), 7.02-7.05 (m, 1H), 6.88 (d,J=8.0 Hz, 2H), 5.44 (s, 2H), 3.68 (s, 3H), 2.99-3.01 (m, 2H), 2.86-2.88(m, 2H), 2.60 (t, J=10.5 Hz, 2H), 2.33 (t, J=10.5 Hz, 2H), 1.89-1.97 (m,4H), 1.73-1.79 (m, 4H); MS, m/z 454.6 [M+H⁺].

Step 41b

Synthesis of4-(4-((5-fluoro-2-(5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((5-fluoro-2-(5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoate(0.096 g, 0.212 mM) with LiOH.H₂O (0.044 g, 1.058 mM), according togeneral procedure D (as described herein above). Yield: 0.083 g, 0.189mM, 89%; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.03 (s, 1H), 7.73-7.78 (m, 1H),7.45 (d, J=9.9 Hz, 1H), 7.25-7.30 (m, 1H), 7.09 (d, J=7.2 Hz, 2H), 6.85(d, J=8.4 Hz, 2H), 5.38 (s, 2H), 2.70-7.90 (m, 4H), 2.40-2.60 (m, 2H),2.15-2.19 (m, 2H), 1.40-1.90 (m, 8H); MS, m/z 440.5 [M+H⁺].

Example 424-(4-((5-Fluoro-2-(5-(1-fluorocyclopropyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoicacid

Step 42a

Synthesis of 1-(5-bromothiophen-2-yl)cyclopropanol

To a stirred solution of ethyl 5-bromothiophene-2-carboxylate (1 g, 4.25mM) and titanium(iv) isopropoxide (0.312 ml, 1.063 mM) in diethyl ether(20 ml), ethylmagnesium bromide (10.63 ml, 10.63 mM) solution was addedat RT and stirred for overnight. The reaction mixture was quenched withsaturated ammonium chloride solution, extracted with ethyl acetate,organic layer washed with brine solution, dried, concentrated andpurified by combiflash to give the title compound. Yield: 0.18 g, 0.822mM, 19.31%; ¹H NMR (CDCl₃, 500 MHz) δ 6.88 (d, J=4.0 Hz, 1H), 6.62 (d,J=3.5 Hz, 1H), 2.59 (s, 1H), 1.25-1.31 (m, 2H), 1.04-1.10 (m, 2H); MSe/z 220.1 [M+H].

Step 42b

Synthesis of 2-bromo-5-(1-fluorocyclopropyl)thiophene

To a stirred solution of 1-(5-bromothiophen-2-yl)cyclopropanol (0.150 g,0.685 mM) in CH₂Cl₂ (5 ml) at −78° C., Diethylaminosulfur trifluoride(DAST) was added slowly (0.090 ml, 0.685 mM) and stirred for 2 h. Thereaction mixture was washed with sodium bicarbonate solution, dried,concentrated and purified to give the title compound. Yield: 0.041 g,0.185 mM, 27.1%; ¹H NMR (CDCl₃, 300 MHz) δ 6.83 (d, J=3.90 Hz, 1H), 6.61(d, J=3.6 Hz, 1H), 1.77-1.21 (m, 2H), 0.86-0.90 (m, 2H); MS (e/z) 244.1[M+Na].

Step 42c

Synthesis of methyl4-(4-((5-fluoro-2-(5-(1-fluorocyclopropyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(0.174 g, 0.407 mM), 2-bromo-5-(1-fluorocyclopropyl)thiophene (0.06 g,0.40 mM), K₂CO₃ (0.113 g, 0.814 mM) in presence oftetrakis(triphenylphosphine)palladium(0) (0.016 g, 0.014 mM) accordingto general procedure C (as described herein above). Yield: 0.082 g,0.185 mM, 68.3%; ¹H NMR (CDCl₃, 500 MHz) δ 7.32-7.38 (m, 2H), 7.07 (d,J=8.5 Hz, 2H), 7.01-7.03 (m, 1H), 6.80-6.81 (m, 4H), 4.98 (s, 2H), 3.67(s, 3H), 2.59 (t, J=7.5 Hz, 2H), 2.32 (t, J=7.5 Hz, 2H), 1.89-1.95 (m,2H), 1.28-1.30 (m, 2H), 0.95-0.98 (m, 2H); MS, m/z 465.4 [M+Na].

Step 42d

Synthesis of4-(4-((5-fluoro-2-(5-(1-fluorocyclopropyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((5-fluoro-2-(5-(1-fluorocyclopropyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoate(0.070 g, 0.158 mM) with LiOH.H₂O (0.033 g, 0.791 mM), according togeneral procedure D (as described herein above). Yield: 0.045 g, 0.105mM, 66.4%; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.03 (s, 1H), 7.40-7.42 (m,2H), 7.19-7.24 (m, 1H), 7.05 (d, J=8.1 Hz, 2H), 6.90 (d, J=3.6 Hz, 1H),6.75-7.85 (m, 3H), 4.92 (s, 2H), 2.40-2.55 (m, 2H), 2.16 (t, J=7.2 Hz,2H), 1.65-1.80 (m, 2H), 1.15-1.25 (m, 2H), 0.08-0.090 (m, 2H); MS, m/z428.5 [M⁺].

Example 434-(4-((4′-(2,2-Difluorocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid

Step 43a

Synthesis of methyl4-(4-((4′-(2,2-difluorocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of1-bromo-4-(2,2-difluorocyclopropyl)benzene (0.054 g, 0.233 mM), methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(0.150 g, 0.350 mM), K₂CO₃ (0.097 g, 0.700 mM) in presence oftetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.012 mM) accordingto general procedure C (as described herein above). Yield: 0.084 g,0.185 mM, 79%; ¹H NMR (300 MHz, CDCl₃) δ 7.25-7.37 (m, 6H), 7.04-7.11(m, 3H), 6.78 (d, J=8.4 Hz, 2H), 4.88 (s, 2H), 3.66 (s, 3H), 2.73-2.84(m, 1H), 2.58 (t, J=7.2 Hz, 2H), 2.31 (t, J=7.5 Hz, 2H), 1.80-1.96 (m,3H), 1.61-1.72 (m, 1H); MS, m/z 478.4 [M+Na⁺].

Step 43b

Synthesis of4-(4-((4′-(2,2-difluorocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((4′-(2,2-difluorocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoate(0.070 g, 0.154 mM) with LiOH.H₂O (0.032 g, 0.770 mM), according togeneral procedure D (as described herein above). Yield: 0.062 g, 0.141mM, 91%; ¹H NMR (300 MHz, DMSO-d₆) δ 12.02 (s, 1H), 7.31-7.45 (m, 6H),7.26-7.29 (m, 1H), 7.07 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 4.91(s, 2H), 3.01-3.08 (m, 1H), 2.45-2.55 (m, 2H), 2.18 (t, J=7.0 Hz, 2H),1.91-2.01 (m, 2H), 1.70-1.76 (m, 2H); MS, m/z 463.2 [M+Na⁺].

Example 444-(4-((2-(5-Cyclopropyl-1,3,4-thiadiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 44a

Synthesis of methyl4-(4-((2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of2-bromo-5-cyclopropyl-1,3,4-thiadiazole (0.048 g, 0.233 mM), methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(0.150 g, 0.350 mM), K₂CO₃ (0.097 g, 0.700 mM) in presence oftetrakis(triphenylphosphine)palladium(0) (0.233 mM) according to generalprocedure C (as described herein above). Yield: 0.064 g, 0.150 mM,64.3%; ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.64 (m, 2H), 7.05-7.15 (m, 3H),6.90 (d, J=8.4 Hz, 2H), 5.42 (s, 2H), 3.67 (s, 3H), 2.59 (t, J=7.5 Hz,2H), 2.40-2.44 (m, 1H), 2.32 (t, J=7.5 Hz, 2H), 1.87-1.97 (m, 2H),1.22-1.29 (m, 4H); MS, m/z 427.4 [M+H⁺].

Step 44b

Synthesis of4-(4-((2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate(0.053 g, 0.124 mM) with LiOH.H₂O (0.026 g, 0.621 mM), according togeneral procedure D (as described herein above). Yield: 0.039 g, 0.095mM, 76%; ¹H NMR (300 MHz, DMSO-d₆) δ 12.02 (s, 1H), 7.77-7.82 (m, 1H),7.50-7.60 (m, 1H), 7.31-7.41 (m, 1H), 7.09 (d, J=8.1 Hz, 2H), 6.86 (d,J=8.4 Hz, 2H), 5.30 (s, 2H), 2.40-2.60 (m, 3H), 2.18 (t, J=7.2 Hz, 2H),1.65-1.80 (m, 2H), 1.20-1.30 (m, 2H), 0.95-1.05 (m, 2H); MS, m/z 413.5[M+H⁺].

Example 454-(4-((2-(5-Cyclopropylthiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 45a

Synthesis of methyl4-(4-((2-(5-cyclopropylthiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of 2-bromo-5-cyclopropylthiazole (0.032g, 0.156 mM), methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(0.100 g, 0.233 mM), potassium carbonate (0.065 g, 0.467 mM) in presenceof tetrakis(triphenylphosphine)palladium(0) (8.99 mg, 7.78 μmol)according to general procedure C (as described herein above). Yield:0.058 g, 0.136 mM, 88%; ¹H NMR (CDCl₃, 300 MHz) δ 7.60-7.65 (m, 1H),7.55 (s, 1H), 7.01-7.09 (m, 3H), 6.88 (d, J=8.4 Hz, 2H), 5.42 (s, 2H),3.66 (s, 3H), 2.59 (t, J=7.5 Hz, 2H), 2.32 (t, J=7.2 Hz, 2H), 2.06-2.13(m, 2H), 1.87-1.97 (m, 2H), 1.05-1.11 (m, 2H), 0.76-0.81 (m, 2H); MS m/z426.4 [M+H⁺].

Step 45b

Synthesis of4-(4-((2-(5-cyclopropylthiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(5-cyclopropylthiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate(0.045 g, 0.106 mM) with LiOH.H₂O (0.022 g, 0.529 mM), according togeneral procedure D (as described herein above). Yield: 0.041 g, 0.100mM, 94%; ¹H NMR (DMSO-d₆, 300 MHz) δ: 12.03 (s, 1H), 7.75-7.79 (m, 1H),7.68 (s, 1H), 7.45-7.50 (m, 1H), 7.27-7.31 (m, 1H), 7.09 (d, J=8.4 Hz,2H), 6.85 (d, J=8.4 Hz, 2H), 5.37 (s, 2H), 2.45-2.55 (m, 2H), 2.15-2.20(m, 3H), 1.71-1.78 (m, 2H), 1.02-1.08 (m, 2H), 0.70-0.75 (m, 2H); MS m/z412.4 [M+H⁺].

Example 464-(4-((5-Fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoicacid

Step 46a

Synthesis of methyl4-(4-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of2-bromo-4,5,6,7-tetrahydrobenzo[d]thiazole (0.034 g, 0.156 mM), methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(0.100 g, 0.233 mM), K₂CO₃ (0.065 g, 0.467 mM) in presence oftetrakis(triphenylphosphine)palladium(0) (8.99 mg, 7.78 μmol) accordingto general procedure C (as described herein above). Yield: 0.054 g,0.123 mM, 79%; ¹H NMR (CDCl₃, 300 MHz) δ 7.63-7.67 (m, 1H), 7.43-7.47(m, 1H), 7.01-7.09 (m, 3H), 6.85 (d, J=8.4 Hz, 2H), 5.42 (s, 2H), 3.66(s, 3H), 2.75-2.85 (m, 4H), 2.59 (t, J=7.5 Hz, 2H), 2.32 (t, J=7.5 Hz,2H), 1.90-1.97 (m, 6H); MS, m/z 440.3 [M+H⁺].

Step 46b

Synthesis of4-(4-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoate(0.040 g, 0.091 mM) with LiOH.H₂O (0.019 g, 0.455 mM), according togeneral procedure D (as described herein above). Yield: 0.034 g, 0.080mM, 88%; ¹H NMR (DMSO-d₆, 300 MHz) δ 12.03 (s, 1H), 7.72-7.80 (m, 1H),7.40-7.50 (m, 1H), 7.25-7.35 (m, 1H), 7.09 (d, J=8.4 Hz, 2H), 6.83 (d,J=8.1 Hz, 2H), 5.37 (s, 2H), 2.77 (s, 2H), 2.67 (s, 2H), 2.40-2.50 (m,2H), 2.10-2.20 (m, 2H), 1.65-1.85 (m, 6H); MS, m/z 425.3 [M⁺].

Example 474-(4-((2-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 47a

Synthesis of methyl4-(4-((2-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of2-bromo-5,6-dihydro-4H-cyclopenta[d]thiazole (0.048 g, 0.233 mM), methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(0.150 g, 0.350 mM), K₂CO₃ (0.032 g, 0.233 mM) in presence oftetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.012 mM) accordingto general procedure C (as described herein above). Yield: 0.084 g,0.197 mM, 85%; ¹H NMR (CDCl₃, 300 MHz) δ 7.65-7.69 (m, 1H), 7.45-7.49(m, 1H), 7.01-7.09 (m, 3H), 6.87 (d, J=8.4 Hz, 2H), 5.42 (s, 2H), 3.66(s, 3H), 2.88-2.99 (m, 4H), 2.48-2.61 (m, 4H), 2.32 (t, J=7.5 Hz, 2H),1.87-1.97 (m, 2H); MS m/z 426.4 [M+H⁺].

Step 47b

Synthesis of4-(4-((2-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate(0.075 g, 0.176 mM) with LiOH.H₂O (0.037 g, 0.881 mM), according togeneral procedure D (as described herein above). Yield: 0.068 g, 0.165mM, 94%; ¹H NMR (DMSO-d₆, 300 MHz) δ 12.04 (s, 1H), 7.75-7.85 (m, 1H),7.40-7.50 (m, 1H), 7.21-7.33 (m, 1H), 7.09 (d, J=7.8 Hz, 2H), 6.84 (d,J=7.8 Hz, 2H), 5.38 (s, 2H), 2.70-3.00 (s, 4H), 2.40-2.50 (m, 4H), 2.17(t, J=6.9 Hz, 2H), 1.73-1.80 (m, 2H); MS, m/z 412.2 [M+H⁺].

Example 484-(4-((2-(6,7-Dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 48a

Synthesis of methyl4-(4-((2-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of2-bromo-6,7-dihydro-4H-pyrano[4,3-d]thiazole (0.051 g, 0.233 mM), methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(0.150 g, 0.350 mM), K₂CO₃ (0.097 g, 0.700 mM) in presence oftetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.012 mM) accordingto general procedure C (as described herein above). Yield: 0.081 g,0.183 mM, 79%; ¹H NMR (CDCl₃ 300 MHz) δ 7.65-7.69 (m, 1H), 7.45-7.49 (m,1H), 7.03-7.10 (m, 3H), 6.85 (d, J=8.4 Hz, 2H), 5.41 (s, 2H), 4.88 (s,2H), 4.07 (t, J=5.7 Hz, 2H), 3.66 (s, 3H), 2.96 (t, J=5.4 Hz, 2H), 2.59(t, J=7.5 Hz, 2H), 2.32 (t, J=7.5 Hz, 2H), 1.87-1.97 (m, 2H); MS, m/z442.1 [M+H⁺].

Step 48b

Synthesis of4-(4-((2-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate(0.071 g, 0.161 mM) with LiOH.H₂O (0.034 g, 0.804 mM), according togeneral procedure D (as described herein above). Yield: 0.061 g, 0.143mM, 89%; ¹H NMR (DMSO-d₆, 300 MHz) δ 12.03 (s, 1H), 7.78-7.82 (m, 1H),7.40-7.50 (m, 1H), 7.28-7.33 (m, 1H), 7.08 (d, J=8.1 Hz, 2H), 6.83 (d,J=8.4 Hz, 2H), 5.38 (s, 2H), 4.80 (s, 2H), 3.93 (t, J=5.4 Hz, 2H),2.70-2.85 (m, 2H), 2.40-2.50 (m, 2H), 2.17 (t, J=7.2 Hz, 2H), 1.70-1.75(m, 2H); MS m/z 428.2 [M+H⁺].

Example 494-(4-((2-(6,7-Dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 49a

Synthesis of methyl4-(4-((2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of6-bromo-2,3-dihydrobenzo[b][1,4]dioxine (0.033 g, 0.156 mM), methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(0.100 g, 0.233 mM), K₂CO₃ (0.065 g, 0.467 mM) in presence oftetrakis(triphenyl)palladium(0) (8.99 mg, 7.78 μmol) according togeneral procedure C (as described herein above). Yield: 0.057 g, 0.131mM, 84%; ¹H NMR (CDCl₃, 300 MHz) δ 7.31-7.34 (m, 2H), 7.00-7.07 (m, 3H),6.77-6.90 (m, 5H), 4.92 (s, 2H), 4.29 (s, 4H), 3.66 (s, 3H), 2.57 (t,J=7.2 Hz, 2H), 2.31 (t, J=7.5 Hz, 2H), 1.86-1.96 (m, 2H); MS, m/z 459.2[M+Na⁺].

Step 49b

Synthesis of4-(4-((2-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of methyl4-(4-((2-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate(0.045 g, 0.103 mM) with LiOH.H₂O (0.022 g, 0.515 mM), according togeneral procedure D (as described herein above). Yield: 0.040 g, 0.095mM, 92%; ¹H NMR (DMSO-d₆, 300 MHz) δ 12.02 (s, 1H), 7.29-7.38 (m, 2H),7.19-7.25 (m, 1H), 7.07 (d, J=8.7 Hz, 2H), 6.78-6.88 (m, 5H), 4.91 (s,2H), 4.24 (s, 4H), 2.40-2.50 (m, 2H), 2.17 (t, J=7.2 Hz, 2H), 1.70-1.77(m, 2H); MS m/z 445.0 [M+Na⁺].

Example 504-(4-((2-(4-Cyclopropylthiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

Step 50a

Synthesis of methyl4-(4-((2-(4-cyclopropylthiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate

The title compound was prepared in an analogous manner as step 1c ofExample 1 involving the reaction of 2-bromo-4-cyclopropylthiazole (0.048g, 0.233 mM), methyl4-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)butanoate(0.150 g, 0.350 mM), potassium carbonate (0.097 g, 0.700 mM) in presenceof tetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.012 mM)according to general procedure C (as described herein above). Yield:0.095 g, 0.223 mM, 96%; ¹H NMR (CDCl₃, 300 MHz) δ 7.68-7.72 (m, 1H),7.48-7.51 (s, 1H), 7.01-7.11 (m, 3H), 6.86-6.91 (m, 3H), 5.42 (s, 2H),3.66 (s, 3H), 2.60 (t, J=7.5 Hz, 2H), 2.33 (t, J=7.5 Hz, 2H), 2.02-2.11(m, 2H), 1.88-1.98 (m, 2H), 0.90-0.99 (m, 4H); MS m/z 426.4 [M+H⁺].

Step 50b

Synthesis of4-(4-((2-(4-cyclopropylthiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction ofmethyl-4-(4-((2-(4-cyclopropylthiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoate(0.090 g, 0.212 mM) with LiOH.H₂O (0.044 g, 1.058 mM), according togeneral procedure D (as described herein above). Yield: 0.060 g, 0.146mM, 68.9%; ¹H NMR (DMSO-d₆, 300 MHz) δ 12.03 (s, 1H), 7.79-7.84 (m, 1H),7.49 (d, J=9.9 Hz, 1H), 7.38 (s, 1H), 7.27-7.32 (m, 1H), 7.09 (d, J=8.1Hz, 2H), 6.85 (d, J=8.1 Hz, 2H), 5.3 (s, 2H), 2.40-2.50 (m, 2H),2.07-2.19 (m, 3H), 1.71-1.76 (m, 2H), 0.82-0.88 (m, 4H); MS m/z 412.2[M+H⁺].

Example 514-(5-((5-Fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)pyridin-2-yl)butanoicacid

Step 51a

Synthesis of 5-(benzyloxy)-2-bromopyridine

6-Bromopyridin-3-ol (3.00 g, 17.24 mmol) and cesium carbonate (8.43 g,25.9 mmol) were stirred in dry acetonitrile (30 mL). Benzyl bromide(3.24 g, 18.97 mmol) was added and stirred at RT for 3 h. Aftercompletion of reaction, the reaction mixture was filtered and washedwith ethyl acetate. The combined organic layers were dried over sodiumsulfate and concentrated to give the title compound,5-(benzyloxy)-2-bromopyridine. Yield: 4.05 g, 89%.

Step 51b

Synthesis of ethyl 4-(5-(benzyloxy)pyridin-2-yl)butanoate

5-(Benzyloxy)-2-bromopyridine (3.00 g, 11.36 mmol) was stirred in dryTHF (60 ml) under argon atmosphere. A 0.5 M solution of(4-ethoxy-4-oxobutyl)zinc(II) bromide in THF (25 mL, 12.49 mmol) wasadded carefully under argon atmosphere. After complete addition of(4-ethoxy-4-oxobutyl)zinc(II) bromide, PEPPSI™-IPr catalyst (0.386 g,0.568 mmol) was added and reaction was stirred overnight at RT. Thereaction mixture was decomposed with saturated ammonium chloridesolution and extracted with ethyl acetate. The organic layer was washedwith brine, dried and concentrated. The crude product was purified oversilica gel using ethyl acetate/petroleum ether as eluent to give thetitle compound, ethyl 4-(5-(benzyloxy)pyridin-2-yl)butanoate. Yield: 2.2g, 64.7%; ¹H NMR (300 MHz, DMSO-d₆): δ 8.31 (m, 1H), 7.45-7.34 (m, 5H),7.22-7.18 (m, 1H), 7.09-7.07 (d, J=8.4 Hz, 1H), 5.10 (s, 2H), 4.17-4.10(q, 2H), 2.81-2.76 (t, 2H), 2.38-2.33 (t, 2H), 2.10-2.00 (m, 2H), 1.28(t, 3H).

Step 51c

Synthesis of ethyl 4-(5-hydroxypyridin-2-yl)butanoate

Ethyl 4-(5-(benzyloxy)pyridin-2-yl)butanoate (0.37 g, 1.23 mmol) wasstirred in dry ethanol (20 mL). Palladium/C (0.02 g) was added carefullyunder argon atmosphere and the reaction mixture was set forhydrogenation at 40 psi for 3 h. After completion of reaction, thereaction mixture was filtered carefully and the filtrate wasconcentrated to give title compound, ethyl4-(5-hydroxypyridin-2-yl)butanoate (0.220 g, 85%). ¹H NMR (300 MHz,DMSO-d₆): δ 8.22 (m, 1H), 7.25-7.23 (m, 1H), 7.13-7.10 (d, J=8.4 Hz,1H), 4.16-4.09 (q, 2H), 2.82-2.77 (t, 2H), 2.378-2.33 (t, 2H), 2.04-2.00(m, 2H), 1.27 (t, 3H).

Step 51d

Synthesis of ethyl4-(5-((2-bromo-5-fluorobenzyl)oxy)pyridin-2-yl)butanoate

1-Bromo-2-(bromomethyl)-4-fluorobenzene (0.282 g, 1.05 mmol) and ethyl4-(5-hydroxypyridin-2-yl)butanoate (0.220 g, 1.05 mmol) were stirred indry acetonitrile. Cesium carbonate was added and reaction mixture wasstirred overnight. After completion of reaction, the reaction mixturewas filtered and the residue was washed with ethyl acetate. The combinedorganic layers were concentrated, purified over combiflash using ethylacetate/pet ether as eluent to give title compound,4-(5-((2-bromo-5-fluorobenzyl)oxy)pyridin-2-yl)butanoate. Yield: 0.320g, 77%; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.33 (m, 1H), 7.58-7.54 (m, 1H),7.13-7.10 (d, J=8.4 Hz, 1H), 4.16-4.09 (q, 2H), 2.82-2.77 (t, 2H),2.378-2.33 (t, 2H), 2.04-2.00 (m, 2H), 1.27 (t, 3H).

Step 51e

Synthesis of ethyl4-(5-((5-fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)pyridin-2-yl)butanoate

The title compound was prepared in an analogous manner as Example 1involving the reaction of ethyl4-(5-((2-bromo-5-fluorobenzyl)oxy)pyridin-2-yl)butanoate (0.100 g, 0.252mmol) with (5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid (0.067 g,0.379 mmol) in presence of Tetrakis(triphenylphosphine)palladium(0)(0.01 g, 0.015 mmol), according to general procedure C (as describedherein above). Yield: 0.057, 50.5%; ¹H NMR (300 MHz, CDCl₃): δ 8.18 (s,1H), 7.32-7.32 (m, 2H), 7.10-7.03 (m, 6H), 4.98 (s, 2H), 4.17-4.09 (q,J=7.2 Hz, 2H), 2.81-2.74 (m, 6H), 2.34 (t, J=7.2 Hz, J=14.7 Hz, 2H),2.08-2.01 (m, 2H), 1.83 (m, 5H), 1.28-1.24 (m, 4H); MS: 448 (M+1).

Step 51f

Synthesis of4-(5-((5-fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)pyridin-2-yl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of ethyl4-(5-((5-fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)pyridin-2-yl)butanoate(0.050 g, 0.11 mmol) with LiOH.H₂O (1.5M, 0.44 mL), according to generalprocedure D (as described herein above). Yield: 0.035 g, 76%; ¹H NMR(300 MHz, DMSO-d₆): δ 12.03 (s, 1H), 8.16 (d, J=2.7 Hz, 1H), 7.45-7.23(m, 8H), 4.96 (s, 2H), 2.71-2.63 (m, 6H), 2.19 (t, J=7.5 Hz, J=14.7 Hz,2H), 1.86-1.81 (m, 2H), 1.71 (s, 4H); MS: 420 (M+1).

Example 524-(5-((2-(2,3-Dihydrobenzofuran-5-yl)-5-fluorobenzyl)oxy)pyridin-2-yl)butanoicacid

Step 52a

Synthesis of ethyl4-(5-((2-(2,3-dihydrobenzofuran-5-yl)-5-fluorobenzyl)oxy)pyridin-2-yl)butanoate

The title compound was prepared in an analogous manner as Example 51involving the reaction of ethyl4-(5-((2-bromo-5-fluorobenzyl)oxy)pyridin-2-yl)butanoate (0.100 g, 0.252mmol) with (2,3-dihydrobenzofuran-5-yl)boronic acid (0.062 g, 0.379mmol) in presence of Tetrakis(triphenylphosphine)palladium(0) (0.01 g,0.015 mmol), according to general procedure C (as described hereinabove). Yield: 0.047 g, 43%; ¹H NMR (300 MHz, CDCl₃): δ 8.17 (s, 1H),7.33-7.26 (m, 2H), 7.16 (s, 1H), 7.10-7.06 (m, 4H), 6.83 (d, J=8.1 Hz,1H), 4.96 (s, 2H), 4.63 (t, J=8.7 Hz, 17.4 Hz, 2H), 4.17-4.09 (q, J=6.9Hz, 2H), 3.23 (t, J=8.7 Hz, J=17.4 Hz, 2H), 2.77 (t, J=7.2 Hz, J=15 Hz,2H), 2.34 (t, J=7.2 Hz, J=14.7 Hz, 2H), 2.08-2.01 (m, 2H), 1.28-1.24 (m,3H); MS: 436 (M+1).

Step 52b

Synthesis of4-(5-((2-(2,3-dihydrobenzofuran-5-yl)-5-fluorobenzyl)oxy)pyridin-2-yl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of ethyl4-(5-((2-(2,3-dihydrobenzofuran-5-yl)-5-fluorobenzyl)oxy)pyridin-2-yl)butanoate(0.040 g, 0.09 mmol) with LiOH.H₂O (1.5M, 0.37 mL), according to generalprocedure D (as described herein above). Yield: 0.030, 80%; ¹H NMR (300MHz, DMSO-d₆): δ 12.04 (s, 1H), 8.15 (s, 1H), 7.42-7.39 (m, 1H),7.36-7.07 (m, 6H), 6.79 (m, 1H), 4.98 (s, 2H), 4.53 (t, J=8.7 Hz, J=17.4Hz, 2H), 3.15 (t, J=8.7 Hz, J=17.1 Hz, 2H), 2.65 (t, J=7.2 Hz, J=15 Hz,2H), 2.20 (t, J=7.2 Hz, J=14.7 Hz, 2H), 1.85-1.81 (m, 2H); MS: 408(M+1).

Example 534-(5-((5-Fluoro-2-(6-methoxypyridin-3-yl)benzyl)oxy)pyridin-2-yl)butanoicacid

Step 53a

Synthesis of ethyl4-(5-((5-fluoro-2-(6-methoxypyridin-3-yl)benzyl)oxy)pyridin-2-yl)butanoate

The title compound was prepared in an analogous manner as Example 51involving the reaction of ethyl4-(5-((2-bromo-5-fluorobenzyl)oxy)pyridin-2-yl)butanoate (0.120 g, 0.303mmol) with (6-methoxypyridin-3-yl)boronic acid (0.069, 0.454 mmol) inpresence of Tetrakis(triphenylphosphine)palladium(0) (0.01 g, 0.015mmol), according to general procedure C (as described herein above).Yield: 0.042 g, 33%; ¹H NMR (300 MHz, CDCl₃): δ 8.14 (m, 2H), 7.80 (d,J=3 Hz, 1H), 7.37-7.31 (m, 2H), 7.20-7.04 (m, 3H), 6.82 (d, J=8.1 Hz,1H), 4.93 (s, 2H), 4.12 (q, J=6.9 Hz, 2H), 3.99 (s, 3H), 2.77 (t, J=7.5Hz, J=15.3 Hz, 2H), 2.35 (t, J=7.5 Hz, J=15 Hz, 2H), 2.08-1.98 (m, 2H),1.28-1.24 (t, J=7.2 Hz, J=14.4, 3H); MS: 425 (M+1).

Step 53b

Synthesis of4-(5-((5-fluoro-2-(6-methoxypyridin-3-yl)benzyl)oxy)pyridin-2-yl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of ethyl4-(5-((2-(2,3-dihydrobenzofuran-5-yl)-5-fluorobenzyl)oxy)pyridin-2-yl)butanoate(0.040 g, 0.09 mmol) with LiOH.H₂O (1.5M, 0.37 mL), according to generalprocedure D (as described herein above). Yield: 0.033, 90%; ¹H NMR (300MHz, DMSO-d₆) δ: 12.04 (s, 1H), 8.18-8.14 (m, 2H), 7.77 (d, J=8.4 Hz,1H), 7.49-7.12 (m, 5H), 6.88 (d, J=8.4 Hz, 1H), 5.00 (s, 2H), 3.86 (s,3H), 2.65 (t, J=7.2 Hz, J=15 Hz, 2H), 2.20 (t, J=7.2 Hz, 14.4 Hz, 2H),1.86-1.81 (m, 2H); MS: 397 (M+1).

Example 544-(5-((4′-Cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)butanoicacid

Step 54a

Synthesis of ethyl4-(5-((4′-cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)butanoate

The title compound was prepared in an analogous manner as Example 51involving the reaction of ethyl4-(5-((2-bromo-5-fluorobenzyl)oxy)pyridin-2-yl)butanoate (0.120 g, 0.303mmol) with (4-cyclopropylphenyl)boronic acid (0.074, 0.454 mmol) inpresence of Tetrakis(triphenylphosphine)palladium(0) (0.01 g, 0.015mmol), according to general procedure C (as described herein above).Yield: 0.050 g, 38%; ¹H NMR (300 MHz, CDCl₃): δ 8.17 (s, 1H), 7.35-7.31(m, 2H), 7.26-7.23 (m, 2H), 7.13-7.05 (m, 5H), 4.96 (s, 2H), 4.12 (q,J=7.2 Hz, 2H), 2.77 (t, J=7.5 Hz, J=15.3 Hz, 2H), 2.34 (t, J=7.2 Hz,14.7 Hz, 2H), 2.08-2.01 (m, 2H), 1.28-1.24 (m, 4H), 1.05-0.99 (m, 2H),0.77-0.74 (m, 2H); MS: 434 (M+1).

Step 54b

Synthesis of4-(5-((4′-cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of ethyl4-(5-((4′-cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)butanoate(0.040, 0.092 mmol) with LiOH.H₂O (1.5M, 0.4 mL), according to generalprocedure D (as described herein above). Yield: 0.033 g, 90%; ¹H NMR(300 MHz, DMSO-d6): δ 12.02 (s, 1H), 8.13 (s, 2H), 7.44-7.21 (m, 5H),7.20-7.14 (m, 3H), 4.98 (s, 2H), 2.65 (t, J=7.5 Hz, J=15 Hz, 2H), 2.20(t, J=7.5 Hz, 14.7 Hz, 2H), 1.99-1.93 (m, 1H), 1.88-1.81 (m, 2H),0.94-0.85 (m, 2H), 0.69-0.68 (m, 2H); MS: 406 (M+1).

Example 554-(5-((5-Fluoro-2-(5-methylthiophen-2-yl)benzyl)oxy)pyridin-2-yl)butanoicacid

Step 55a

Synthesis of ethyl4-(5-((5-fluoro-2-(5-methylthiophen-2-yl)benzyl)oxy)pyridin-2-yl)butanoate

The title compound was prepared in an analogous manner as Example 51involving the reaction of ethyl4-(5-((2-bromo-5-fluorobenzyl)oxy)pyridin-2-yl)butanoate (0.150 g, 0.379mmol) with (5-methylthiophen-2-yl)boronic acid (0.161 g, 01.131 mmol) inpresence of Tetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.019mmol), according to general procedure C (as described herein above).Yield: 0.065 g, 41.5%; ¹H NMR (300 MHz, CDCl₃): δ 8.24 (d, J=2.7 Hz,1H), 7.45-7.40 (m, 1H), 7.35-7.31 (m, 1H), 7.15-7.07 (m, 3H), 6.84 (d,J=3.6 Hz, 1H), 6.74 (s, 1H), 5.11 (s, 2H), 4.17-4.10 (m, 2H), 2.78 (q,J=7.5 Hz, J=15.3, 2H), 2.52 (s, 3H), 2.35 (t, J=7.5 Hz, J=15 Hz, 2H),2.07 (q, J=8.1 Hz, 2H), 1.29 (t, J=6.9 Hz, 14.1 Hz, 3H).

Step 55b

Synthesis of4-(5-((5-fluoro-2-(5-methylthiophen-2-yl)benzyl)oxy)pyridin-2-yl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of ethyl4-(5-((5-fluoro-2-(5-methylthiophen-2-yl)benzyl)oxy)pyridin-2-yl)butanoate(0.060 g, 0.145 mmol) with LiOH.H₂O (1.5M, 0.58 mL), according togeneral procedure D (as described herein above). Yield: 0.034 g, 61%; ¹HNMR (300 MHz, DMSO-d₆): δ 12.04 (s, 1H), 8.22 (s, 1H), 7.51-7.47 (m,2H), 7.35-7.19 (m, 5H), 5.11 (s, 2H), 2.67 (t, J=7.2 Hz, J=15 Hz, 2H),2.44 (s, 3H), 2.21 (t, J=7.5 Hz, 14.7 Hz, 2H), 1.87-1.82 (m, 2H); MS:386 (M+1).

Example 564-(5-((2-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)pyridine-2-yl)butanoicacid

Step 56a

Synthesis of ethyl4-(5-((2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)pyridin-2-yl)butanoate

The title compound was prepared in an analogous manner as Example 51involving the reaction of ethyl4-(5-((2-bromo-5-fluorobenzyl)oxy)pyridin-2-yl)butanoate (0.120 g, 0.303mmol), with bicyclo[4.2.0]octa-1(6),2,4-trien-3-ylboronic acid (0.067 g,0.454 mmol) in presence of Tetrakis(triphenylphosphine)palladium(0)(0.017 g, 0.015 mmol), according to general procedure C (as describedherein above). Yield: 0.100 g, 79% yield; ¹H NMR (300 MHz, CDCl₃) δ:8.16 (s, 1H), 7.30-7.27 (m, 2H), 7.14-7.01 (m, 6H), 4.96 (s, 2H),4.16-4.09 (q, J=7.2 Hz, 2H), 3.23 (s, 4H), 2.79-2.74 (t, J=7.5 Hz,J=15.3 Hz, 2H), 2.37-2.32 (d, J=7.5 Hz, J=15 Hz, 2H), 2.08-1.98 (m, 2H),1.28-1.24 (m, 3H); MS: 420 (M+1).

Step 56b

Synthesis of4-(5-((2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)pyridine-2-yl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of ethyl4-(5-((2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)pyridin-2-yl)butanoate(0.09 g, 0.215 mmol) with LiOH.H₂O (1.5M, 0.858 mL, 1.287 mmol),according to general procedure D (as described herein above). Yield:0.080 g, 95%; ¹H NMR (300 MHz, DMSO-d₆): δ: 12.03 (s, 1H), 7.41-7.32 (m,1H), 7.30-7.08 (m, 8H), 4.97 (s, 2H), 2.64 (t, J=7.2 Hz, J=14.7 Hz, 2H),2.19 (t, J=7.5 Hz, J=14.4 Hz, 2H), 1.85-1.80 (m, 2H), 1.23-1.15 (m, 4H);MS: 392 (M+1).

Example 574-(5-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)butanoicacid

Step 57a

Synthesis of ethyl4-(5-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)butanoate

The title compound was prepared in an analogous manner as Example 51involving the reaction of ethyl4-(5-((2-bromo-5-fluorobenzyl)oxy)pyridin-2-yl)butanoate (0.120 g, 0.303mmol), with (4-(1-cyanocyclopropyl)phenyl)boronic acid (0.085 g, 0.454mmol) in presence of Tetrakis(triphenylphosphine)palladium(0) (0.017 g,0.015 mmol), according to general procedure C (as described hereinabove). Yield: 0.115 g, 83%; ¹H NMR (300 MHz, CDCl₃): δ 8.15 (s, 1H),7.31-7.26 (m, 6H), 7.15-7.06 (m, 3H), 4.92 (s, 2H), 4.17 (q, J=7.2 Hz,2H), 2.77 (t, J=7.2 Hz, J=15 Hz, 2H), 2.35 (t, J=7.5 Hz, J=15 Hz, 2H),2.06-2.01 (m, 3H), 1.81-1.77 (m, 2H), 1.49-1.45 (m, 2H), 1.28-1.24 (m,2H); MS: 459 (M+1).

Step 57b

Synthesis of4-(5-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of ethyl4-(5-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)butanoate(0.105 g, 0.229 mmol) with LiOH.H₂O (0.916 mL, 1.374 mmol), according togeneral procedure D (as described herein above). Yield: 0.090 g, 91%; ¹HNMR (300 MHz, DMSO-d₆): δ 12.02 (s, 1H), 8.13 (d, J=2.7 Hz, 1H),7.47-7.30 (m, 6H), 7.25-7.21 (m, 2H), 7.14-7.11 (m, 1H), 4.99 (s, 2H),2.65 (t, J=7.2 Hz, J=14.7 Hz, 2H), 2.20 (t, J=7.5 Hz, J=14.7 Hz, 2H),1.86-1.75 (m, 4H), 1.56-1.51 (m, 2H); MS: 431 (M+1).

Example 584-(5-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)pyridin-2-yl)butanoicacid

Step 58a

Synthesis of5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzaldehyde

5-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(0.200 g, 0.800 mmol), 2-bromo-4,5,6,7-tetrahydrobenzo[d]thiazole (0.209g, 0.960 mmol) and potassium carbonate (0.276 g, 1.999 mmol) werestirred in dioxane:water (4:1) mixture (5 mL) and the reaction mixturewas purged with argon for 5 minutes. Palladium tetrakis (0.011 g, 0.040mmol) was added and again purged with argon for 5 minutes. The reactionmixture was heated at 110° C. for 2 h. After completion of reaction, thereaction mixture was concentrated and purified by column chromatographyto obtain the title compound,5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzaldehyde. Yield:0.089 g, 43%; ¹H NMR (300 MHz, DMSO-d₆): δ 10.31 (s, 1H), 7.89-7.84 (m,1H), 7.65-7.56 (m, 2H), 2.84-2.77 (m, 4H), 1.83 (s, 4H); MS (m/z): 262(M+1).

Step 58b

Synthesis of(5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)phenyl)methanol

To a solution of5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzaldehyde (0.080g, 0.306 mmol) in methanol was added sodium borohydride (0.014 g, 0.367mmol) at 0° C. The reaction mixture was stirred at RT for 1 h. Aftercompletion of reaction, the reaction mixture was concentrated,triturated with water, extracted with ethyl acetate, dried over sodiumsulfate, concentrated and purified by column chromatography to providethe title compound,(5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)phenyl)methanol.Yield: 0.077 g, 96%; ¹H NMR (300 MHz, CDCl₃): δ 7.68 (dd, J=5.7, 8.7 Hz,1H), 7.18 (dd, J=2.4, 9 Hz, 1H), 7.09-7.03 (m, 1H), 6.37 (s, 1H), 4.56(s, 2H), 1.91 (s, 4H), 1.58 (s, 4H); MS (m/z): 264 (M+1).

Step 58c

Synthesis of2-(2-(bromomethyl)-4-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole

To a solution of(5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)phenyl)methanol(0.070 g, 0.266 mmol) in DCM was added tribromophosphine (0.072 g, 0.266mmol) at 0° C. The reaction mixture was stirred at room temperature for1 h. After completion of reaction, the reaction mixture was diluted withDCM and washed with aqueous NaHCO₃. The aqueous layer was extracted withDCM. The organic layers were combined, dried over sodium sulfate andconcentrated to obtain title compound,2-(2-(bromomethyl)-4-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole.Yield: 64 mg, 0.196 mmol, 73.8% yield.

Step 58d

Synthesis of ethyl4-(5-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)pyridin-2-yl)butanoate

A mixture of2-(2-(bromomethyl)-4-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole(0.100 g, 0.307 mmol), ethyl 4-(5-hydroxypyridin-2-yl)butanoate (0.071g, 0.337 mmol) and cesium carbonate (0.250 g, 0.766 mmol) inacetonitrile (5 mL) was stirred at RT for 2 h. The reaction mixture wasfiltered through Celite® and washed with ethyl acetate. The organiclayers were combined, concentrated and purified by column chromatographyto obtain the title compound, ethyl4-(5-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)pyridin-2-yl)butanoate.Yield: 0.037 g, 26.6%; ¹H NMR (300 MHz, CDCl₃): δ 8.28 (d, J=3 Hz, 1H),7.70-7.65 (m, 1H), 7.48-7.45 (m, 1H), 7.20-7.16 (m, 1H), 7.09-7.05 (m,2H), 5.50 (s, 2H), 4.15 (q, J=6.9 Hz, 2H), 2.83-2.76 (m, 6H), 2.36 (t,J=7.5 Hz, J=15 Hz, 2H), 2.10-2.00 (m, 2H), 1.92-1.91 (m, 4H), 1.35-1.24(m, 3H); MS: 455 (M+1).

Step 58e

Synthesis of4-(5-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)pyridin-2-yl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of ethyl4-(5-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)pyridin-2-yl)butanoate(0.030 g, 0.066 mmol) with LiOH.H₂O (0.264 mL, 0.396 mmol), according togeneral procedure D (as described herein above). Yield: 0.025 g, 89%; ¹HNMR (300 MHz, DMSO-d₆): δ 12.4 (s, 1H), 8.17 (s, 1H), 7.81-7.76 (m, 1H),7.53-7.50 (m, 1H), 7.36-7.27 (m, 2H), 7.18-7.16 (m, 1H), 5.46 (s, 2H),2.78 (s, 2H), 2.69-2.64 (m, 4H), 2.27-2.19 (m, 2H), 1.90-1.82 (m, 6H);MS: 427 (M+1).

Example 594-(5-((5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzyl)oxy)pyridin-2-yl)butanoicacid

Step 59a

Synthesis of5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzaldehyde

To a solution of 2-bromo-5-(1-methylcyclopropyl)thiophene (0.660 g, 3.04mmol) and (4-fluoro-2-formylphenyl)boronic acid (0.510 g, 3.04 mmol) in15 mL dioxane:water (4:1) mixture was added potassium carbonate (1.05 g,7.60 mmol) and the mixture was purged with argon for 5 minutes. To theresulting solution palladium tetrakistriphenylphosphine (0.211 g, 0.182mmol) was added and the mixture was heated at 80° C. for 1 h. Aftercompletion of reaction, the reaction was quenched with water, extractedwith ethyl acetate, dried over sodium sulfate, concentrated and purifiedby column chromatography to obtain the title compound,5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzaldehyde as yellowsemisolid. Yield: 0.316 g, 40%; ¹H NMR (300 MHz, CDCl₃) δ; 10.16 (s,1H), 7.68-7.64 (m, 1H), 7.54-7.46 (m, 2H), 7.39-7.31 (m, 1H), 6.83-6.80(m, 1H), 2.17-2.08 (m, 1H), 1.53 (s, 3H), 1.03-1.00 (m, 2H), 0.99-0.91(m, 2H); MS (m/z): 261.0 (M+1).

Step 59b

Synthesis of(5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)phenyl)methanol

5-Fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzaldehyde (0.180 g,0.691 mmol) was stirred in methanol (2 mL) at 0° C. and sodiumborohydride (0.026 g, 0.691 mmol) was added slowly. After completeaddition of sodium borohydride, the reaction mixture was stirred at RTfor 1 h. After completion of the reaction, the reaction mixture wasconcentrated under vacuum, the residue was quenched with water andextracted with ethyl acetate (10 mL×3). The organic layers werecombined, dried over Na₂SO₄ and concentrated to obtain the titlecompound,(5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)phenyl)methanol.Yield: 0.150 g, 83%; ¹H NMR (300 MHz, CDCl₃): δ 7.37-7.28 (m, 3H),7.13-6.98 (m, 1H), 6.86-6.85 (m, 1H), 4.77-4.76 (m, 2H), 1.52 (s, 3H),0.99-0.89 (m, 4H).

Step 59c

Synthesis of2-(2-(bromomethyl)-4-fluorophenyl)-5-(1-methylcyclopropyl)thiophene

To a solution of(5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)phenyl)methanol (0.180g, 0.686 mmol) in DCM (2 mL), was added tribromophosphine (0.186 g,0.686 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30minutes. After completion of reaction, the reaction mixture was dilutedwith DCM and washed with ice cold solution of NaHCO₃ and then extractedwith DCM. The organic layers were combined, washed with brine solutiondried over anhydrous sodium sulfate and concentrated to obtain the titlecompound,2-(2-(bromomethyl)-4-fluorophenyl)-5-(1-methylcyclopropyl)thiophene.

Step 59d

Ethyl4-(5-((5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzyl)oxy)pyridin-2-yl)butanoate

2-(2-(Bromomethyl)-4-fluorophenyl)-5-(1-methylcyclopropyl)thiophene(0.200 g, 0.615 mmol), ethyl 4-(5-hydroxypyridin-2-yl)butanoate (0.142g, 0.676 mmol) and cesium carbonate (0.501 g, 1.537 mmol) were stirredin acetonitrile (10 mL) at RT for 2 h. The reaction mixture was filteredthrough celite. The filtrate was washed with ethyl acetate, concentratedand the crude mass purified by column chromatography, to get ethyl4-(5-((5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzyl)oxy)pyridin-2-yl)butanoate.Yield: 0.013 g, 4.66%; ¹H NMR (300 MHz, CDCl₃): δ 8.24 (d, J=2.4 Hz,1H), 7.45-7.40 (m, 1H), 7.34-7.30 (m, 1H), 7.15-7.04 (m, 3H), 6.82 (d,J=3.6 Hz, 1H), 6.73 (d, J=3.6 Hz, 1H), 5.11 (s, 2H), 4.17-4.10 (m, 2H),2.81-2.74 (m, 2H), 2.36 (d, J=7.5 Hz, J=15 Hz, 2H), 2.10-2.00 (m, 2H),1.50 (s, 3H), 1.31-1.24 (m, 3H), 0.96-0.86 (m, 4H); MS (m/z): 454 (M+1).

Step 59e

Synthesis of4-(5-((5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzyl)oxy)pyridin-2-yl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of ethyl4-(5-((5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzyl)oxy)pyridin-2-yl)butanoate (0.010 g, 0.022 mmol) with LiOH.H₂O (0.088 mL, 0.132 mmol),according to general procedure D (as described herein above). Yield:0.09 g, 96%; ¹H NMR (300 MHz, DMSO-d₆): δ 8.14 (s, 1H), 7.46-7.32 (m,2H), 7.24-7.05 (m, 3H), 6.82-6.79 (m, 1H), 6.74-6.58 (m, 1H), 5.13 (s,2H), 3.02-2.85 (m, 2H), 2.43-2.39 (m, 2H), 2.08-2.02 (m, 2H), 1.24-1.17(m, 3H), 1.02-0.901 (m, 4H); MS (m/z): 426 (M+1).

Example 604-(5-((4-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)pyridin-2-yl)butanoicacid

Step 60a

Synthesis of4-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzaldehyde

2-Bromo-4,5,6,7-tetrahydrobenzo[d]thiazole (1.732 g, 7.94 mmol),(5-fluoro-2-formylphenyl)boronic acid (2.00 g, 11.91 mmol) and potassiumcarbonate (3.29 g, 23.82 mmol) were stirred in a solvent mixture ofdioxane (20 mL) and water (25 mL) and purged with argon for 5 minutes.To the resulting reaction mixture was added palladiumtetrakistriphenylphosphine (0.459 g, 0.397 mmol) and argon was purgedfor 5 minutes. The reaction mixture was heated overnight at 80° C. thencooled to room temperature and filtered through Celite®. The filtratewas concentrated to give residue, which was dissolved in ethyl acetate,washed with water, brine solution, dried over sodium sulfate,concentrated and purified by flash chromatography to obtain the titlecompound,4-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzaldehyde as asolid. Yield: 1.6 g, 77% yield; ¹H NMR (300 MHz, CDCl₃): δ 10.49 (s,1H), 8.09-8.04 (m, 1H), 7.41-7.37 (m, 1H), 7.24-7.18 (m, 1H), 2.88 (s,4H), 1.94 (s, 4H); MS: 262 (M+1).

Step 60b

Synthesis of(4-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)phenyl)methanol

To a stirred solution of4-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzaldehyde (1.7 g,6.51 mmol) in MeOH (25 mL) at 0° C. was added sodium borohydride (0.123g, 3.25 mmol) portion wise and the reaction mixture was stirred for 2 h.After completion of reaction, the reaction mixture was concentrated,acidified by 1N HCl solution, extracted with ethyl acetate, washed withbrine solution, dried, concentrated and purified to obtain the titlecompound(4-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)phenyl)methanol assolid. Yield: 1.3 g, 76%; ¹H NMR (300 MHz, CDCl₃): δ 7.45-7.36 (m, 2H),7.11-7.05 (m, 1H), 6.25-6.20 (t, 1H, OH peak), 4.60-4.57 (d, 2H), 2.86(s, 4H), 1.93 (s, 4H); MS: 264.1 (M+1).

Step 60c

Synthesis of2-(2-(bromomethyl)-5-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole

To a solution of(4-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)phenyl)methanol(0.195 g, 0.741 mmol) in DCM (2 mL), was added tribromophosphine (0.070mL, 0.741 mmol) at 0° C. The reaction mixture was stirred at 0° C. for30 minutes. After completion of reaction, the reaction mixture waspoured in ice cold water, neutralized with NaHCO₃ and extracted withDCM. The organic layers were combined, washed with brine solution, driedover sodium sulfate and concentrated under vacuum to obtain the titlecompound,2-(2-(bromomethyl)-5-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole.Yield: 0.196 g, 81%.

Step 60d

Ethyl4-(5-((4-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)pyridin-2-yl)butanoate

A mixture of2-(2-(bromomethyl)-4-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole(0.196 g, 0.601 mmol), ethyl 4-(5-hydroxypyridin-2-yl)butanoate (0.126g, 0.601 mmol) and cesium carbonate (0.489 g, 1.502 mmol) were stirredin acetonitrile (5 mL) at RT for 2 h. The reaction mixture was filteredthrough Celite® and washed with ethyl acetate. The filtrate wasconcentrated and purified by column chromatography (0-20%EtOAc:petroleum ether), to obtain the title compound, ethyl4-(5-((4-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)pyridin-2-yl)butanoate.Yield: 0.142 g, 52.0%; ¹H NMR (300 MHz, CDCl₃): δ 8.26 (d, J=2.7 Hz,1H), 7.68-7.64 (m, 1H), 7.44-7.40 (m, 1H), 7.18-7.06 (m, 3H), 5.45 (s,2H), 4.15 (q, J=7.2 Hz, 2H), 2.84-2.76 (m, 6H), 2.36 (t, 2H), 2.10-2.02(m, 2H), 1.90 (s, 4H), 1.29-1.24 (m, 3H); MS: 455 (M+1).

Step 60e

Synthesis of4-(5-((4-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)pyridin-2-yl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of ethyl4-(5-((4-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)pyridin-2-yl)butanoate(0.132 g, 0.290 mmol) with LiOH.H₂O (1.162 ml, 1.742 mmol), according togeneral procedure D (as described herein above). Yield: 0.100 g, 81%; ¹HNMR (300 MHz, DMSO-d₆): δ 12.06 (s, 1H), 8.14 (d, J=2.7 Hz, 1H),7.73-7.68 (m, 1H), 7.57-7.54 (m, 1H), 7.38-7.26 (m, 2H), 6.82 (d, J=3.6Hz, 1H), 5.40 (s, 2H), 2.78 (s, 2H), 2.69-2.60 (m, 4H), 2.21 (d, J=7.5Hz, J=15 Hz, 2H), 1.99-1.77 (m, 6H); MS: 427 (M+1).

Example 614-(5-((2-(5-cyclopropylthiophen-2-yl)-4-fluorobenzyl)oxy)pyridin-2-yl)butanoicacid

Step 61a

Synthesis of 2-(5-cyclopropylthiophen-2-yl)-4-fluorobenzaldehyde

To a solution of 2-bromo-5-cyclopropylthiophene (2 g, 9.85 mmol) and(5-fluoro-2-formylphenyl)boronic acid (2.150 g, 12.80 mmol) in 10 mLdioxane:water (4:1) mixture was added potassium carbonate (3.40 g, 24.62mmol) and the mixture was purged with argon for 5 minutes. To theresulting solution palladiumtetrakistriphenylphosphine (0.683 g, 0.591mmol) was added and argon was purged for 5 minutes. The reaction mixturewas heated at 80° C. for 1 h. After completion of reaction, the reactionmixture was quenched with water, extracted with ethyl acetate, driedover sodium sulfate, concentrated and purified by column chromatographyon silica gel to obtain the title compound2-(5-cyclopropylthiophen-2-yl)-4-fluorobenzaldehyde and colorless thickliquid. Yield: 1.74 g, 7.06 mmol, 71.7%.

Step 61b

Synthesis of (2-(5-cyclopropylthiophen-2-yl)-4-fluorophenyl)methanol

To a solution of 2-(5-cyclopropylthiophen-2-yl)-4-fluorobenzaldehyde(2.3 g, 9.34 mmol) in methanol was added sodium borohydride (0.353 g,9.34 mmol) and the reaction mixture was stirred at RT for 2 h. Aftercompletion of reaction, the reaction mixture was concentrated, dilutedwith acidified water (acidified with 1N HCl) and extracted with ethylacetate to obtain the title compound(2-(5-cyclopropylthiophen-2-yl)-4-fluorophenyl)methanol. Yield: 2.2 g,8.86 mmol, 95%.

Step 61c

Synthesis of 2-(2-(bromomethyl)-5-fluorophenyl)-5-cyclopropylthiophene

To a solution of (2-(5-cyclopropylthiophen-2-yl)-4-fluorophenyl)methanol(0.250 g, 1.007 mmol) in DCM, was added tribromophosphine (0.096 mL,1.007 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30minutes. After completion, the reaction mixture was poured in ice-coldwater and neutralized with NaHCO₃ and extracted with DCM. The organiclayers were combined, washed with brine solution, dried over sodiumsulfate and concentrated to obtain the title compound,2-(2-(bromomethyl)-5-fluorophenyl)-5-cyclopropylthiophene.

Step 61d

Synthesis of ethyl4-(5-((2-(5-cyclopropylthiophen-2-yl)-4-fluorobenzyl)oxy)pyridin-2-yl)butanoate

2-(2-(Bromomethyl)-5-fluorophenyl)-5-cyclopropylthiophene (0.200 g,0.643 mmol), ethyl 4-(5-hydroxypyridin-2-yl)butanoate (0.134 g, 0.643mmol) and cesium carbonate (0.523 g, 1.607 mmol) were stirred inacetonitrile (5 mL) at RT for 2 h. The reaction mixture was filteredthrough Celite® and washed with ethyl acetate. The filtrate wasconcentrated and purified by column chromatography (0-20% EtOAc:petether), to obtain the title compound, ethyl4-(5-((2-(5-cyclopropylthiophen-2-yl)-4-fluorobenzyl)oxy)pyridin-2-yl)butanoate.Yield: 0.168 g, 59.5%; ¹H NMR (300 MHz, CDCl₃): δ 8.26 (d, J=2.4 Hz,1H), 7.56-7.51 (m, 1H), 7.21-7.04 (m, 4H), 6.91 (d, J=3.3 Hz, 1H), 6.73(d, J=3.6 Hz, 1H), 5.06 (s, 2H), 4.15 (q, J=6.9 Hz, 2H), 2.79 (t, J=7.5Hz, 15.3 Hz, 2H), 2.36 (t, J=7.5 Hz, J=15 Hz, 2H), 2.08-2.06 (m, 3H),1.29-1.24 (m, 3H), 1.04-0.99 (m, 2H), 0.76-0.74 (m, 2H); MS: 440 (M+1).

Step 61e

Synthesis of4-(5-((2-(5-cyclopropylthiophen-2-yl)-4-fluorobenzyl)oxy)pyridin-2-yl)butanoicacid

The title compound was prepared in an analogous manner as Example 1involving the reaction of ethyl4-(5-((2-(5-cyclopropylthiophen-2-yl)-4-fluorobenzyl)oxy)pyridin-2-yl)butanoate(0.160 g, 0.364 mmol) with LiOH.H₂O (1.456 mL, 2.184 mmol), according togeneral procedure D (as described herein above). Yield: 0.139 g, 93%yield; ¹H NMR (300 MHz, DMSO-d₆): δ 12.04 (s, 1H), 8.21 (s, 1H),7.69-7.64 (m, 1H), 7.35-7.16 (m, 4H), 7.05 (d, J=3.6 Hz, 1H), 6.82 (d,J=3.6 Hz, 1H), 5.06 (s, 2H), 2.68 (t, J=7.5 Hz, 15 Hz, 2H), 2.24-2.19(m, 2H), 2.10-1.99 (m, 1H), 1.88-1.83 (m, 2H), 1.23-1.15 (m, 4H).

Example 62

Biological Assays

Representative compounds of formula (I) of the present invention(referred to as test compounds) were tested for their activity using theassays and the methods described below

Beta (β) arrestin 2 Interaction Assay (BRET assay) was performed usingCHO-K1 cells stably expressing the GPR120L receptor usingβ-galactosidase (Beta gal) enzyme fragment complementation assay. Themeasurement of GPR120 activation upon agonist activation was directlyprovided by β-arrestin recruitment. One day before the β-arrestin 2assay, CHO-K1 cells were seeded and incubated overnight at 37° C. in a5% CO₂ humidified atmosphere. Cells were treated with the test compoundsin the various concentrations ranging from 30 μM to 1 nM and incubatedfor 2 hours for GPCR (GPR120) activation. Extent of Arrestin recruitmentwas measured by adding detection reagents for Beta gal complementationassay and was further incubated for 1 hour. The chemi-luminescent signalwas detected on Polar Star (BMG Labtech). The dose-response curve wasanalyzed using Sigma Plot/Graph Pad. The EC₅₀ (concentration of the testcompounds where 50% of compounds' maximal activity is observed) valueswere calculated from the dose-response curve.

TABLE 1 EC₅₀ values of compounds of Examples Examples No. EC₅₀ (nM)Example 1 +++ Example 2 ++ Example 3 +++ Example 4 +++ Example 5 +++Example 6 ++ Example 7 +++ Example 8 +++ Example 9 +++ Example 10 +++Example 11 +++ Example 12 ++ Example 13 + Example 14 ++ Example 15 +Example 16 ++ Example 17 + Example 18 +++ Example 19 ++ Example 20 ++Example 21 + Example 22 +++ Example 23 +++ Example 24 +++ Example 25 ++Example 26 +++ Example 27 +++ Example 28 +++ Example 29 +++ Example 30+++ Example 31 +++ Example 32 + Example 33 +++ Example 34 ++ Example 35+++ Example 36 +++ Example 37 ++ Example 38 + Example 39 + Example 40+++ Example 41 +++ Example 42 + Example 43 +++ Example 44 +++ Example 45+++ Example 46 +++ Example 47 +++ Example 48 ++ Example 49 +++ Example50 ++ +++ corresponds to EC₅₀ ranging from 10 nM to 500 nM; ++corresponds to EC₅₀ ranging from 500 nM to 5000 nM; + corresponds toEC₅₀ ranging from 5000 nM to 50000 nM;Conclusion:

The EC₅₀ values determined for the compounds of the present invention isindicative of GPR120 agonist activity of the compounds of the presentinvention.

We claim:
 1. A compound of formula (I):

or a stereoisomer, a tautomer, a geometrical isomer, a pharmaceuticallyacceptable salt, a pharmaceutically acceptable solvate, a prodrug, anN-oxide, a S-oxide or a carboxylic acid isostere thereof; wherein: RingA is a saturated or unsaturated optionally substituted 4- to 10-memberedcarbocycle; an optionally substituted 5- to 10-membered heteroaryl; or asaturated or partly saturated or unsaturated optionally substituted 5-to 10-membered heterocycle; wherein said heteroaryl or heterocyclecontain 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;Ring B and Ring C are independently selected from the group consistingof optionally substituted (C₆-C₁₀)aryl and optionally substituted 6- to10-membered heteroaryl which contains 1, 2 or 3 heteroatomsindependently selected from the group consisting of N, O and S; X is—(CR⁸R⁹)_(p)—O—, (CR⁸R⁹)_(p)—S—, —(CR⁸R⁹)_(p)—N(R¹⁰)—, —O—(CR⁸R⁹)_(p)—,—S—(CR⁸R⁹)_(p)— or —N(R¹⁰)—(CR⁸R⁹)_(p); Y is —(CR¹⁴R¹⁵)_(g)—; Q is—CO₂M, —CONH₂, —CONH[(C₁-C₆)alkyl], —CON[(C₁-C₆)alkyl]₂ or—CONHSO₂(C₁-C₆)alkyl; M is hydrogen, deuterium or (C₁-C₆)alkyl; R¹ is

wherein

is point of attachment to Ring A; J is —CH₂—, —CHF—, —CF₂—,—CH[(C₁-C₆)alkyl]—, or —C[(C₁-C₆)alkyl]₂-; “-----” represents anoptional bond; R^(a) is hydrogen, (C₁-C₆)alkyl or halo(C₁-C₆)alkyl; R²is selected from the group consisting of hydrogen, halogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heteroaryl, heterocyclyl,(C₆-C₁₀)aryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C₆-C₁₀)aryl-, (C₆-C₁₀)aryloxy,heterocyclyl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heterocyclyl,heteroaryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heteroaryl, cyano, —NR¹⁰R¹¹,—C(O)NR¹⁰R¹¹, —C(S)NR¹⁰R¹¹, —S(O)_(t)R¹² and —C(O)R¹³; or R¹ and R² arecombined together with one or two atoms of Ring A to form: a 3- to8-membered partly unsaturated or saturated carbocycle wherein the saidcarbocycle or heterocycle can be unsubstituted or substituted with theone or more groups independently selected from the group consisting of(C₁-C₆)alkenyl, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy,halogen, cyano, oxo, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heteroaryl andheterocyclyl and wherein Ring A together with R¹ and R² does not form anunsubstituted tetrahydronaphthyl group; R³ at each occurrence, isindependently selected from the group consisting of hydrogen, halogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heteroaryl, heterocyclyl,(C₆-C₁₀)aryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,heterocyclyl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heterocyclyl-,heteroaryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heteroaryl, cyano, —NR¹⁰R¹¹,—C(O)NR¹⁰R¹¹, —C(S)NR¹⁰R¹¹, —S(O)_(t)R¹² and —C(O)R¹³; R⁴ at eachoccurrence, is independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy,halogen, cyano, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heteroaryl,heterocyclyl, (C₆-C₁₀)aryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C₆-C₁₀)aryl,(C₆-C₁₀)aryloxy, heterocyclyl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heterocyclyl,heteroaryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heteroaryl, —NR¹⁰R¹¹, —S(O)_(t)R¹²and —C(O)R¹³; R⁵ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, hydroxy, cyano, —COR¹⁰, —NR¹⁰R¹¹, —CONR¹⁰R¹¹,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,—S(O)_(t)R¹² and —C(O)R¹³; R⁶ and R⁷ are independently selected from thegroup consisting of hydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl andhalogen; R⁸ and R⁹ are independently selected from the group consistingof hydrogen, deuterium, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and halogen; orR⁸ and R⁹ together with the carbon atom they are attached to form: i) a3- to 5-membered saturated carbocycle selected from the group consistingof cyclopropane, cyclobutane, cyclopentane and cyclohexane; or ii) a 4-to 6-membered saturated heterocycle selected from the group consistingof oxetane, thietane, azetidine, tetrahydrofuran, tetrahydrothiophene,pyrolidine and piperidine; R¹⁰ is hydrogen, hydroxy, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,heterocyclyl, heteroaryl, (C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C₆-C₁₀)aryl, heterocyclyl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-heterocyclyl, heteroaryl-(C₁-C₆)alkyl or(C₁-C₆)alkyl-heteroaryl or —S(O)_(t)R¹²; R¹¹ is hydrogen, hydroxy,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl,(C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C₆-C₁₀)aryl,heterocyclyl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heterocyclyl,heteroaryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heteroaryl or —S(O)_(t)R¹²; or R¹⁰and R¹¹ are combined together to form 3- to 8-membered saturated orunsaturated ring which contains 1, 2 or 3 heteroatoms independentlyselected from N, O and S; R¹² and R¹³ are independently selected fromthe group consisting of hydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl,(C₆-C₁₀)aryl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C₆-C₁₀)aryl,heterocyclyl-(C₁-C₆)alkyl, (C₁-C₆)alkyl-heterocyclyl,heteroaryl-(C₁-C₆)alkyl and (C₁-C₆)alkyl-heteroaryl; R¹⁴ and R¹⁵ areindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl and halogen; or R¹⁴ and R¹⁵ are combinedtogether to form a 3- to 5-membered saturated carbocycle or 4- to6-membered saturated heterocycle which optionally contains 1 or 2heteroatoms independently selected from the group consisting of N, O andS; wherein the said carbocycle or heterocycle can be unsubstituted orsubstituted; g is 2, 3, 4, 5 or 6; m is 0, 1 or 2; n is 0, 1 or 2; p is1, 2 or 3; r is 0, 1, 2, 3 or 4; t is 0, 1 or 2; wherein (C₁-C₆)alkyl isunsubstituted or substituted with one or more groups independentlyselected from the group consisting of (C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, heterocyclyl,heteroaryl, amino, cyano, nitro, —NH(C₁-C₆)alkyl, —N[(C₁-C₆)alkyl]₂,—C(O)(C₁-C₆)alkyl, —C(O)O(C₁-C₆)alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl,—C(O)N[(C₁-C₆)alkyl]₂ and —C(O)NHSO₂(C₁-C₆)alkyl; (C₃-C₁₀)cycloalkyl isunsubstituted or substituted with one or more groups independentlyselected from the group consisting of (C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, amino,cyano and nitro; carbocycle is unsubstituted or substituted with one ormore groups independently selected from the group consisting of(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy, halogen, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, (C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl, heteroaryl,heterocyclyl, amino, cyano, nitro, —C(O)O(C₁-C₆)alkyl, —C(O)NR¹⁰R¹¹ and—S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are as defined above;(C₆-C₁₀)aryl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, amino,cyano, nitro, —C(O)O(C₁-C₆)alkyl, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; whereinR¹⁰, R¹¹, R¹² and t are as defined above; heterocyclyl is unsubstitutedor substituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, halo(C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,heterocyclyl, heteroaryl, amino, cyano, nitro, —C(O)NR¹⁰R¹¹ and—S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are as defined above;heteroaryl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,heterocyclyl, heteroaryl, amino, cyano, nitro, —C(O)NR¹⁰R¹¹ and—S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are as defined above.
 2. Acompound according to claim 1, wherein R¹ is

wherein

is point of attachment to Ring A; J is —CH₂—, —CHF—, —CF₂—,—CH[(C₁-C₆)alkyl], or —C[(C₁-C₆)alkyl]₂-; “-----” represents an optionalbond; R⁵, R⁶, R⁷ and r are as defined in claim 1; R² is selected fromthe group consisting of hydrogen, halogen, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, (C₃-C₁₀)cycloalkyl,(C₆-C₁₀)aryl, heteroaryl, heterocyclyl, (C₆-C₁₀)aryl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C₆-C₁₀)aryl-, (C₆-C₁₀)aryloxy, heterocyclyl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-heterocyclyl, heteroaryl-(C₁-C₆)alkyl,(C₁-C₆)alkyl-heteroaryl, cyano, —NR¹⁰R¹¹, —C(O)NR¹⁰R¹¹, —C(S)NR¹⁰R¹¹,—S(O)_(t)R¹² and —C(O)R¹³.
 3. A compound according to claim 1, whereinR¹ and R² are combined together with one or two atoms of Ring A to form:a 3- to 8-membered, partly saturated or saturated carbocycle wherein thecarbocycle or heterocycle is unsubstituted or substituted with the oneor more groups independently selected from the group consisting of(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, halogen, cyano,(C₆-C₁₀)aryl, heteroaryl and heterocyclyl and wherein Ring A togetherwith R¹ and R² does not form an unsubstituted tetrahydronaphthyl group.4. A compound according to claim 1, wherein Ring A is a 6- to10-membered aromatic carbocycle; a 5- or 6-membered heteroaryl or a 5-or 6-membered heterocyclyl wherein heteroaryl and heterocyclyl contain1, 2 or 3 heteroatoms independently selected from the group consistingof N, O and S; wherein aromatic carbocycle is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy, halogen,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl,heteroaryl, heterocyclyl, amino, cyano, nitro, —C(O)O(C₁-C₆)alkyl,—C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are asdefined above; heteroaryl is unsubstituted or substituted with one ormore groups independently selected from the group consisting of(C₁-C₆)alkyl, halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, heterocyclyl, heteroaryl, amino, cyano, nitro,—C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are asdefined above; heterocyclyl is unsubstituted or substituted with one ormore groups independently selected from the group consisting of(C₁-C₆)alkyl, halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl,heteroaryl, amino, cyano, nitro, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; whereinR¹⁰, R¹¹, R¹² and t are as defined above.
 5. A compound according toclaim 1, wherein Ring A is 6- to 10-membered aromatic carbocycle,wherein aromatic carbocycle is unsubstituted or substituted with one ormore groups independently selected from the group consisting of(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy, halogen, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, (C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl, heteroaryl,heterocyclyl, amino, cyano, nitro, —C(O)O(C₁-C₆)alkyl, —C(O)NR¹⁰R¹¹ and—S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are as defined above.
 6. Acompound according to claim 1, wherein Ring A is phenyl; wherein phenylis unsubstituted or substituted with one or more groups independentlyselected from the group consisting of (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,hydroxy, halogen, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₆-C₁₀)aryl,(C₃-C₁₀)cycloalkyl, heteroaryl, heterocyclyl, amino, cyano, nitro,—C(O)O(C₁-C₆)alkyl, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹²and t are as defined above.
 7. A compound according to claim 1, whereinRing A is a 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatomsindependently selected from the group consisting of N, O and S; whereinheteroaryl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,heterocyclyl, heteroaryl, amino, cyano, nitro, —C(O)NR¹⁰R¹¹ and—S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are as defined above;heterocyclyl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, amino,cyano, nitro, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and tare as defined above.
 8. A compound according to claim 1, wherein Ring Ais 5- or 6-membered heteroaryl selected from the group consisting ofpyrrole, pyrazole, imidazole, pyrazine, furan, thiophene, oxazole,oxadiazole, thiazole, thiadiazole, pyridine, pyrimidine, and tetrazole;wherein each of the heteroaryl ring is unsubstituted or substituted withone or more groups independently selected from the group consisting of(C₁-C₆)alkyl, halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, heterocyclyl, heteroaryl, amino, cyano, nitro,—C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are asdefined above.
 9. A compound according to claim 1, wherein Ring B is(C₆-C₁₀)aryl; wherein (C₆-C₁₀)aryl is unsubstituted or substituted withone or more groups independently selected from the group consisting of(C₁-C₆)alkyl, halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl,heteroaryl, amino, cyano, nitro, —C(O)O(C₁-C₆)alkyl, —C(O)NR¹⁰R¹¹ and—S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are as defined above.
 10. Acompound according to claim 1, wherein Ring B is phenyl; wherein phenylis unsubstituted or substituted with one or more groups independentlyselected from the group consisting of (C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, amino,cyano, nitro, —C(O)O(C₁-C₆)alkyl, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; whereinR¹⁰, R¹¹, R¹² and t are as defined above.
 11. A compound according toclaim 1, wherein Ring B is 6- to 10-membered heteroaryl which contains1, 2 or 3 heteroatoms independently selected from N, O and S, whereinheteroaryl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,heterocyclyl, heteroaryl, amino, cyano, nitro, —C(O)NR¹⁰R¹¹ and—S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are as defined above.
 12. Acompound according to claim 1, wherein Ring B is a 6-membered heteroarylwhich contains 1, 2 or 3 N; wherein said heteroaryl is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, halo(C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, heterocyclyl, heteroaryl, amino,cyano, nitro, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and tare as defined above.
 13. A compound according to claim 1, wherein RingC is 6- to 10-membered heteroaryl which contains 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein heteroaryl isunsubstituted or substituted with one or more groups independentlyselected from the group consisting of (C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,heterocyclyl, heteroaryl, amino, cyano, nitro, —C(O)NR¹⁰R¹¹ and—S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are as defined above.
 14. Acompound according to claim 1, wherein Ring C is a 6-membered heteroarylwhich contains 1, 2 or 3 N; wherein said heteroaryl is unsubstituted orsubstituted with one or more groups with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,heterocyclyl, heteroaryl, amino, cyano, nitro, —C(O)NR¹⁰R¹¹ and—S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are as defined above.
 15. Acompound according to claim 1, wherein Ring C is (C₆-C₁₀)aryl; which isunsubstituted or substituted with one or more groups independentlyselected from the group consisting of (C₁-C₆)alkyl, halogen,halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, amino,cyano, nitro, —C(O)O(C₁-C₆)alkyl, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; whereinR¹⁰, R¹¹, R¹² and t are as defined above.
 16. A compound according toclaim 1, wherein Ring C is phenyl; wherein phenyl is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, halo(C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,heterocyclyl, heteroaryl, amino, cyano, nitro, —C(O)O(C₁-C₆)alkyl,—C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are asdefined above.
 17. A compound according to claim 1, wherein Ring C isunsubstituted phenyl.
 18. A compound according to claim 1, wherein X is—(CR⁸R⁹)_(p)—O—, wherein R⁸, R⁹ and p are as defined in claim
 1. 19. Acompound according to claim 1, wherein Y is —(CR¹⁴R¹⁵)_(g)—; wherein R¹⁴and R¹⁵ are independently hydrogen or (C₁-C₆)alkyl.
 20. A compound whichis4-(4-((2-(5-(1-Cyanocyclopropyl)thiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;3-(4-((2-(5-(1-Cyanocyclopropyl)thiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)propanoicacid;4-(4-((4-Fluoro-4′-(1-methylcyclopropyl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid;4-(4-((4′-(1-Cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid;3-(4-((4′-(1-Cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoicacid;3-(4-((2-(6-(1-Cyanocyclopropyl)pyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)propanoicacid;4-(4-((4′-Cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid;4-(4-((2-(2,3-Dihydro-1H-inden-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;4-(4-((5-Fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid;4-(4-((2-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;4-(4-((2-(5-Cyclopropylthiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;4-(4-((5-Fluoro-2-(5-(1-hydroxycyclobutyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoicacid;3-(4-((4-Fluoro-4′-(oxetan-3-yl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoicacid;3-(4-((4-Fluoro-4′-(1-hydroxycyclobutyl)-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoicacid;3-(4-((4′-(5,5-Dimethylcyclopent-1-en-1-yl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoicacid;4-(4-((4′-Cyclohexyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid;3-(4-((5-Fluoro-2-(6-(oxetan-3-yl)pyridin-3-yl)benzyl)oxy)phenyl)propanoicacid;3-(5-((4′-(1-Cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)propanoicacid;4-(4-((4-(4-(1-Cyanocyclopropyl)phenyl)pyridin-3-yl)methoxy)phenyl)butanoicacid;3-(5-((2-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)pyridin-2-yl)propanoicacid;3-(4-((2-(4-(1-Cyanocyclopropyl)phenyl)pyridin-3-yl)methoxy)phenyl)propanoicacid;4-(4-((2-(2,3-Dihydrobenzofuran-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;4-(4-((5-Fluoro-2-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)benzyl)oxy)phenyl)butanoicacid;4-(4-((2-(6,7-Dihydro-5H-cyclopenta[b]pyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;4-(4-((5-Fluoro-2-(7-methylene-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoicacid;4-(4-((2-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)benzyl)oxy)phenyl)butanoicacid;4-(4-((2-(5,6,7,8-Tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid;4-(4-((2-(5-Cyclobutylthiophen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;4-(4-((4′-Cyclopropyl-4-fluoro-3′-methyl-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid;4-(4-((2-(6-Cyclopropylpyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;4-(4-((2-(2-Cyclopropylpyrimidin-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;4-(4-((2-(4-Cyclopropylthiazol-5-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid; 4-(4-((2-(2,3-Dihydro-1H-inden-5-yl)benzyl)oxy)phenyl)butanoicacid;4-(4-((5-Fluoro-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid;4-(4-((2-(7,8-Dihydronaphthalen-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;4-(4-((5-Fluoro-2-(5-methylene-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid;4-(4-((5-Fluoro-2-(5-methyl-7,8-dihydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid;4-(4-((5-Fluoro-2-(5-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid;4-(4-((5-Fluoro-2-(5-methoxy-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)phenyl)butanoicacid;4-(4-((5-Fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoicacid;4-(4-((5-Fluoro-2-(5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoicacid;4-(4-((5-Fluoro-2-(5-(1-fluorocyclopropyl)thiophen-2-yl)benzyl)oxy)phenyl)butanoicacid;4-(4-((4′-(2,2-Difluorocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)phenyl)butanoicacid;4-(4-((2-(5-Cyclopropyl-1,3,4-thiadiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;4-(4-((2-(5-Cyclopropylthiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;4-(4-((5-Fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)phenyl)butanoicacid;4-(4-((2-(5,6-Dihydro-4H-cyclopenta[d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;4-(4-((2-(6,7-Dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;4-(4-((2-(6,7-Dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;4-(4-((2-(4-Cyclopropylthiazol-2-yl)-5-fluorobenzyl)oxy)phenyl)butanoicacid;4-(5-((5-Fluoro-2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)oxy)pyridin-2-yl)butanoicacid;4-(5-((2-(2,3-Dihydrobenzofuran-5-yl)-5-fluorobenzyl)oxy)pyridin-2-yl)butanoicacid;4-(5-((5-Fluoro-2-(6-methoxypyridin-3-yl)benzyl)oxy)pyridin-2-yl)butanoicacid;4-(5-((4′-Cyclopropyl-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)butanoicacid;4-(5-((5-Fluoro-2-(5-methylthiophen-2-yl)benzyl)oxy)pyridin-2-yl)butanoicacid;4-(5-((2-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-fluorobenzyl)oxy)pyridine-2-yl)butanoicacid;4-(5-((4′-(1-cyanocyclopropyl)-4-fluoro-[1,1′-biphenyl]-2-yl)methoxy)pyridin-2-yl)butanoicacid;4-(5-((5-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)pyridin-2-yl)butanoicacid;4-(5-((5-fluoro-2-(5-(1-methylcyclopropyl)thiophen-2-yl)benzyl)oxy)pyridin-2-yl)butanoicacid; or4-(5-((4-fluoro-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzyl)oxy)pyridin-2-yl)butanoicacid; and4-(5-((2-(5-cyclopropylthiophen-2-yl)-4-fluorobenzyl)oxy)pyridin-2-yl)butanoicacid or a stereoisomer, a tautomer or a geometrical isomer thereof; or apharmaceutically acceptable salt, a pharmaceutically acceptable solvatethereof.
 21. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of Formula (I) according to claim 1, or astereoisomer, a tautomer, a geometrical isomer, a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof; and atleast one pharmaceutically acceptable carrier or excipient.
 22. Acompound according to claim 1, wherein Ring A is a 6- to 10-memberedaromatic carbocycle; a 5- or 6-membered heteroaryl or a 5- or 6-memberedheterocyclyl wherein heteroaryl and heterocyclyl contain 1, 2 or 3heteroatoms independently selected from the group consisting of N, O andS; wherein the aromatic carbocycle, heteroaryl or heterocyclyl issubstituted with R¹; wherein R¹ is

wherein

is point of attachment to Ring A; J is —CH₂—, —CHF—, —CF₂—,—CH[(C₁-C₆)alkyl], —C[(C₁-C₆)alkyl]₂; r is 0, 1, 2, 3, or 4, “-----”represents a bond, and the remaining variables are defined as inclaim
 1. 23. A compound according to claim 1, wherein R¹ and R² arecombined together with one or two atoms of Ring A to form a 3- to8-membered partly unsaturated or saturated carbocycle; wherein the saidcarbocycle can be unsubstituted or substituted with the one or moregroups independently selected from the group consisting of(C₁-C₆)alkenyl, (C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, hydroxy, halogen,cyano, oxo, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heteroaryl andheterocyclyl; and wherein Ring A together with R¹ and R² does not forman unsubstituted tetrahydronaphthyl group.
 24. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula (I) according to claim 20, or a stereoisomer, a tautomer, ageometrical isomer, a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof; and at least onepharmaceutically acceptable carrier or excipient.
 25. The compound ofclaim 22, wherein R⁵, R⁶, R⁷ are hydrogen, J is —CH₂—, and r is
 0. 26. Acompound according to claim 23, wherein R¹ and R² are combined togetherwith one or two atoms of Ring A to form a 3- to 8-membered partlyunsaturated or saturated carbocycle, and wherein Ring A together with R¹and R² does not form an unsubstituted tetrahydronaphthyl group.
 27. Thecompound of claim 22, wherein Ring A is a 5- or 6-membered heteroarylcontaining 1, 2 or 3 heteroatoms independently selected from the groupconsisting of N, O and S; wherein heteroaryl is unsubstituted orsubstituted with one or more groups independently selected from thegroup consisting of (C₁-C₆)alkyl, halogen, halo(C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, heterocyclyl, heteroaryl, amino,cyano, nitro, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and tare as defined above; heterocyclyl is unsubstituted or substituted withone or more groups independently selected from the group consisting of(C₁-C₆)alkyl, halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl,heteroaryl, amino, cyano, nitro, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; whereinR¹⁰, R¹¹, R¹² and t are as defined above.
 28. The compound of claim 23,wherein Ring A is a 5- or 6-membered heteroaryl containing 1, 2 or 3heteroatoms independently selected from the group consisting of N, O andS; wherein heteroaryl is unsubstituted or substituted with one or moregroups independently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,heterocyclyl, heteroaryl, amino, cyano, nitro, —C(O)NR¹⁰R¹¹ and—S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and t are as defined above;heterocyclyl is unsubstituted or substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, halo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, heterocyclyl, heteroaryl, amino,cyano, nitro, —C(O)NR¹⁰R¹¹ and —S(O)_(t)R¹²; wherein R¹⁰, R¹¹, R¹² and tare as defined above.